Goodman and Gilman Manual of Pharmacology and Therapeutics
Hormones and Hormone Antagonists
Agents Affecting Mineral Ion Homeostasis and Bone Turnover
PHYSIOLOGY OF MINERAL ION HOMEOSTASIS
Elemental calcium is essential for a variety of biological functions. Its ionized form, Ca2+, is an important component of current flow across excitable membranes. Ca2+ is vital for muscle contraction, fusion, and release of storage vesicles. In the submicromolar range, intracellular Ca2+ acts as a critical second messenger (see Chapter 3). In extracellular fluid, millimolar concentrations of Ca2+ promote blood coagulation and support the formation and continuous remodeling of the skeleton.
In the face of millimolar extracellular Ca2+, intracellular free Ca2+ is maintained at a low level, ~100 nM in cells in their basal state, by active extrusion by Ca2+–ATPases, by Na+/Ca2+ exchange, and by accumulation into cellular storage networks such as the sarcoplasmic reticulum. Changes in cytosolic Ca2+ (whether released from intracellular stores or entering via membrane Ca2+ channels) can modulate effector targets, often by interacting with the Ca2+-binding protein calmodulin. The rapid association–dissociation kinetics of Ca2+ and the relatively high affinity and selectivity of Ca2+-binding domains permit effective regulation of Ca2+ over the 100 nM to 1 ~ range.
The body content of calcium in healthy adult men and women, respectively, is ~1300 and 1000 g, of which >99% is in bone and teeth. Ca2+ in extracellular fluids is stringently regulated within narrow limits. In adult humans, the normal serum Ca2+ concentration ranges from 8.5-10.4 mg/dL (4.25-5.2 mEq/L, 2.1-2.6 mM) and includes 3 distinct chemical forms of Ca2+: ionized (50%), protein-bound (40%), and complexed (10%). Thus, whereas total plasma Ca2+ concentration is ~2.5 mM, the concentration of ionized Ca2+ in plasma is ~1.2 mM. The various pools of Ca2+ are illustrated schematically in Figure 44–1. Only diffusible Ca2+ (i.e., ionized plus complexed) can cross cell membranes. Albumin accounts for some 90% of the serum Ca2+ bound to plasma proteins; a change of plasma albumin concentration of 1.0 g/dL from the normal value of 4.0 g/dL can be expected to alter total Ca2+ concentration by ~0.8 mg/dL. The remaining 10% of the serum Ca2+ is complexed with small polyvalent anions, primarily phosphate and citrate. The degree of complex formation depends on the ambient pH and the concentrations of ionized Ca2+ and complexing anions. Ionized Ca2+ is the physiologically relevant component, mediates calcium’s biological effects, and, when perturbed, produces the characteristic signs and symptoms of hypo- or hypercalcemia. The extracellular Ca2+ concentration is tightly controlled by hormones that affect calcium entry at the intestine and its exit at the kidney; when needed, these same hormones regulate withdrawal from the large skeletal reservoir.
Figure 44–1 Pools of calcium in serum. Concentrations are expressed as mg/dL on the left-hand axis and as mM on the right. The total serum calcium concentration is 10 mg/dL or 2.5 mM, divided into 3 pools: protein-bound (40%), complexed with small anions (10%), and ionized calcium (50%). The complexed and ionized pools represent the diffusable forms of calcium.
Calcium Stores. The skeleton contains 99% of total body calcium in a crystalline form resembling the mineral hydroxyapatite; other ions, including Na+, K+, Mg2+, and F–, also are present in the crystal lattice. The steady-state content of Ca2+ in bone reflects the net effect of bone resorption and bone formation.
Calcium Absorption and Excretion. In the U.S., ~75% of dietary Ca2+ is obtained from milk and dairy products. The adequate intake value for Ca2+ is 1300 mg/day in adolescents and 1000 mg/day in adults. After age 50, the adequate intake is 1200 mg/day. Figure 44–2 illustrates the components of whole-body daily Ca2+ turnover. Ca2+ enters the body only through the intestine. Active vitamin D–dependent Ca2+ transport occurs in the proximal duodenum, whereas facilitated diffusion throughout the small intestine accounts for most total Ca2+ uptake. This uptake is counterbalanced by an obligatory daily intestinal Ca2+ loss of ~150 mg/day that reflects the Ca2+ content of mucosal and biliary secretions and in sloughed intestinal cells. The efficiency of intestinal Ca2+ absorption is inversely related to calcium intake. Thus, a diet low in calcium leads to a compensatory increase in fractional absorption owing partly to activation of vitamin D. Disease states associated with steatorrhea, chronic diarrhea, or malabsorption promote fecal loss of Ca2+. Drugs such as glucocorticoids and phenytoin depress intestinal Ca2+ transport.
Figure 44–2 Whole body daily turnover of calcium. (Adapted with permission from Yanagawa N, Lee DBN. Renal handling of calcium and phosphorus. In: Coe FL, Favus MJ, eds. Disorders of Bone and Mineral Metabolism, New York: Raven Press; 1992, pp 3–40.)
Urinary Ca2+ excretion is the net difference between the quantity filtered at the glomerulus and the amount reabsorbed. About 9 g of Ca2+ are filtered each day, of which >98% is reabsorbed in the tubules. The efficiency of reabsorption is highly regulated by parathyroid hormone (PTH) and is influenced by filtered Na+, the presence of nonreabsorbed anions, and diuretic agents (see Chapter 25).
Phosphate is present in plasma, extracellular fluid, cell membrane phospholipids, intracellular fluid, collagen, and bone tissue. More than 80% of total body phosphorus is found in bone; ~15% is in soft tissue. Additionally, phosphate is a dynamic constituent of intermediary and energy metabolism and as a key regulator of enzyme activity when transferred by protein kinases from ATP to phosphorylatable serine, threonine, and tyrosine residues. Biologically, phosphorus (P) exists in both organic and inorganic (Pi) forms. Organic forms include phospholipids and various organic esters. In extracellular fluid, the bulk of phosphorus is present as inorganic phosphate in the form of NaH2PO4 and Na2HPO4. The aggregate level of inorganic phosphate (Pi) modifies tissue concentrations of Ca2+ and plays a major role in renal H+ excretion. Within bone, phosphate is complexed with Ca2+ as hydroxyapatites and as calcium phosphate.
Absorption, Distribution, and Excretion. Phosphate is absorbed from and, to a limited extent, secreted into the GI tract. Phosphate is a ubiquitous component of ordinary foods; even an inadequate diet rarely causes phosphate depletion. Transport of phosphate from the intestinal lumen is an active, energy-dependent process that is regulated by several factors, primarily vitamin D, which stimulates absorption. In adults, about two-thirds of ingested phosphate is absorbed and is excreted almost entirely into the urine. In growing children, phosphate balance is positive, and plasma concentrations of phosphate are higher than in adults.
Phosphate excretion in the urine represents the difference between the amount filtered and that reabsorbed. More than 90% of plasma phosphate is freely filtered at the glomerulus, and 80% is actively reabsorbed, predominantly in the proximal convoluted tubule. Renal phosphate absorption is regulated by a variety of hormones and other factors; the most important are PTH and dietary phosphate, with extracellular volume and acid–base status playing lesser roles. Dietary phosphate deficiency upregulates renal phosphate transporters and decreases excretion, whereas a high-phosphate diet increases phosphate excretion; these changes are independent of any effect on plasma Pi, Ca2+, or PTH. PTH increases urinary phosphate excretion by blocking phosphate absorption. Expansion of plasma volume increases urinary phosphate excretion.
ROLE OF PHOSPHATE IN URINE ACIDIFICATION., Phosphate is concentrated progressively in the renal tubule and becomes the most abundant buffer system in the distal tubule and terminal nephron. The exchange of H+ and Na+ in the tubular urine converts Na2HPO4 to NaH2PO4, permitting the excretion of large amounts of acid without lowering the urine pH to a degree that would block H+ transport.
PHARMACOLOGICAL ACTIONS OF PHOSPHATE., Phosphate salts are employed as mild laxatives (see Chapter 46).
HORMONAL REGULATION OF CALCIUM AND PHOSPHATE HOMEOSTASIS
A number of hormones interact to regulate extracellular Ca2+ and phosphate balance. The most important are PTH and 1,25-dihydroxyvitamin D3 (calcitriol), which regulate mineral homeostasis by effects on the kidney, intestine, and bone (Figure 44–3).
Figure 44–3 Calcium homeostasis and its regulation by parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D. PTH has stimulatory effects on bone and kidney, including the stimulation of 1α-hydroxylase activity in kidney mitochondria leading to the increased production of 1,25-dihydroxyvitamin D (calcitriol) from 25-hydroxycholecalciferol, the monohydroxylated vitamin D metabolite (Figure 44–5). Calcitriol is the biologically active metabolite of vitamin D.
PTH is a polypeptide that helps to regulate plasma Ca2+ by affecting bone resorption/formation, renal Ca2+ excretion/reabsorption, and calcitriol synthesis (thus, GI Ca2+ absorption).
PTH is single polypeptide chain of 84 amino acids with molecular mass of ~9500 Da. Biological activity is associated with the N-terminal portion of the peptide; residues 1–27 are required for optimal binding to the PTH receptor and hormone activity. Derivatives lacking the first and second residue bind to PTH receptors but do not activate the cyclic AMP or IP3–Ca2+ signaling pathways. The PTH fragment lacking the first 6 amino acids inhibits PTH action.
SYNTHESIS AND SECRETION., PTH is synthesized as a 115–amino acid peptide called preproparathyroid hormone, which is converted to proparathyroid hormone by cleavage of 25 amino-terminal residues in the endoplasmic reticulum. Proparathyroid hormone is converted in the Golgi complex to PTH by cleavage of 6 amino acids. PTH(1-84) resides within secretory granules until it is discharged into the circulation. PTH(1-84) has a t1/2 in plasma of ~4 min; removal by the liver and kidney accounts for ~90% of its clearance. Proteolysis of PTH generates smaller fragments (e.g., a 33–36 amino acid N-terminal fragment that is fully active, a larger C-terminal peptide, and PTH[7-84]). PTH(7-84) and other amino-truncated PTH fragments are normally cleared from the circulation predominantly by the kidneys, whereas intact PTH is also removed by extrarenal mechanisms.
Physiological Functions., The primary function of PTH is to maintain a constant concentration of Ca2+ and Pi in the extracellular fluid. The principal processes regulated are renal Ca2+ and Pi absorption, and mobilization of bone Ca2+ (see Figure 44–3). The actions of PTH are mediated by at least 2 receptors: the PTH1 and the PTH2 receptor. Both of these are GPCRs that can couple with Gs and Gq in cell-type specific manners. PTH also can activate phospholipase D through a G12/13–RhoA pathway. A third receptor, the CPTH receptor, interacts with forms of PTH that are truncated in the amino-terminal region, contain most of the carboxy terminus, and are inactive at the PTH1 receptor; these CPTH receptors reportedly are expressed on osteocytes.
Regulation of Secretion., Plasma Ca2+ is the major factor regulating PTH secretion. As the concentration of Ca2+ diminishes, PTH secretion increases; hypocalcemia induces parathyroid hypertrophy and hyperplasia. Conversely, if the concentration of Ca2+ is high, PTH secretion decreases. Changes in plasma Ca2+ regulate PTH secretion by the plasma membrane–associated calcium-sensing receptor(CaSR) on parathyroid cells. The CaSR is a GPCR that couples with Gq and Gi. Occupancy of the CaSR by Ca2+ stimulates the Gq-PLC-IP3-Ca2+ pathway leading to activation of PKC; this results in inhibition of PTH secretion, an unusual case in which elevation of cellular Ca2+ inhibits secretion (another being the granular cells in the juxtaglomerular complex of the kidney, where elevation of cellular Ca2+ inhibits renin secretion). Simultaneous activation of the Gi pathway by Ca2+ reduces cyclic AMP synthesis and lowers the activity of PKA, also a negative signal for PTH secretion. Conversely, reduced occupancy of CaSR by Ca2+ reduces signaling through Gi and Gq, thereby promoting PTH secretion. Other agents that increase parathyroid cell cyclic AMP levels, such as β adrenergic receptor agonists and dopamine, also increase PTH secretion, but much less than does hypocalcemia. The active vitamin D metabolite, 1,25-dihydroxyvitamin D (calcitriol), directly suppresses PTH gene expression. Severe hypermagnesemia or hypomagnesemia can inhibit PTH secretion.
Effects on Bone., Chronically elevated PTH enhances bone resorption and thereby increases Ca2+ delivery to the extracellular fluid, whereas intermittent exposure to PTH promotes anabolic actions. The primary skeletal target cell for PTH is the osteoblast.
Effects on Kidney., In the kidney, PTH enhances the efficiency of Ca2+ reabsorption, inhibits tubular reabsorption of phosphate, and stimulates conversion of vitamin D to its biologically active form, 1,25-dihydroxy vitamin D3 (calcitriol; see Figure 44–3). As a result, filtered Ca2+ is avidly retained, and its concentration increases in plasma, whereas phosphate is excreted, and its plasma concentration falls. Newly synthesized 1,25-dihydroxy vitamin D3 interacts with specific high-affinity receptors in the intestine to increase the efficiency of intestinal Ca2+ absorption, thereby contributing to the increase in plasma (Ca2+).
Calcitriol Synthesis., The final step in the activation of vitamin D to calcitriol occurs in kidney proximal tubule cells. Three primary regulators govern the enzymatic activity of the 25-hydroxyvitamin D3-1 α-hydroxylase that catalyzes this step: Pi, PTH, and Ca2+ (see later for further discussion). Reduced circulating or tissue phosphate content rapidly increases calcitriol production, whereas hyperphosphatemia or hypercalcemia suppresses it. PTH powerfully stimulates calcitriol synthesis. Thus, when hypocalcemia causes a rise in PTH concentration, both the PTH-dependent lowering of circulating Pi and a more direct effect of the hormone on the 1 α-hydroxylase lead to increased circulating concentrations of calcitriol.
Integrated Regulation of Extracellular [Ca2+] by PTH., Even modest reductions of serum Ca2+ stimulate PTH secretion. With prolonged hypocalcemia, the renal 1 α-hydroxylase is induced, enhancing the synthesis and release of calcitriol that directly stimulates intestinal Ca2+ absorption (see Figure 44–3), and delivery of calcium from bone into the extracellular fluid is augmented. With prolonged and severe hypocalcemia, new bone remodeling units are activated to restore circulating Ca2+ concentrations, albeit at the expense of skeletal integrity. When plasma Ca2+ activity rises, PTH secretion is suppressed, and tubular Ca2+ reabsorption decreases. The reduction in circulating PTH promotes renal phosphate conservation, and both the decreased PTH and the increased phosphate depress calcitriol production and thereby decrease intestinal Ca2+ absorption. Finally, bone remodeling is suppressed. These integrated physiological events ensure a coherent response to positive or negative excursions of plasma Ca2+ concentrations.
Vitamin D is a hormone rather than a vitamin, and it plays an active role in Ca2+ homeostasis. The biological actions of vitamin D are mediated by the vitamin D receptor (VDR), a nuclear receptor. Vitamin D is the name applied to 2 related fat-soluble substances, vitamin D3 (cholecalciferol) and vitamin D2 (ergocalciferol) (Figure 44–4), that share the capacity to prevent or cure rickets. In humans there is no practical difference between the antirachitic potencies of vitamin D2 and vitamin D3. Therefore, “vitamin D” is used here as a collective term for vitamins D2 and D3.
Figure 44–4 Photobiology and pathways of vitamin D production and metabolism.
The principal provitamin found in animal tissues is 7-dehydrocholesterol, which is synthesized in the skin. Exposure of the skin to sunlight converts 7-dehydrocholesterol to cholecalciferol (vitamin D3). Ergosterol, present only in plants and fungi, is the provitamin for vitamin D2 (ergocalciferol). Vitamin D2 is the active constituent of a number of commercial vitamin preparations and is in irradiated bread and irradiated milk.
HUMAN REQUIREMENTS AND UNITS., Although sunlight provides adequate vitamin D supplies in the equatorial belt, in temperate climates insufficient cutaneous solar radiation, especially in winter, may necessitate dietary vitamin D supplementation. Serum levels of vitamin D vary widely, likely reflecting genetic background, diet, latitude, time spent out of doors, body size, developmental stage, and state of health, as well as plasma levels of vitamin D binding protein, a specific α-globulin. The actions of vitamin D may vary with the expression of components of the synthetic and action pathways of vitamin D. Other factors contributing to the rise of vitamin D deficiency may include diminished consumption of vitamin D–fortified foods owing to concerns about fat intake; reduced intake of dairy products; increased use of sunscreens and decreased exposure to sunlight to reduce the risk of skin cancer and prevent premature aging from exposure to ultraviolet radiation; and an increased prevalence and duration of exclusive breast-feeding (human milk is a poor source of vitamin D). There is no consensus regarding optimal vitamin D intake. The U.S. Institute of Medicine suggests achieving a serum level for 25-OH vitamin D of 50 nmol/L (20 ng/mL) and recommends a daily intake for most children and adults of 600 IU (15 µg) per day (Table 44–1).
Recommended Daily Allowance of Ca2+ and Vitamin D
ADME., Vitamins D2 and D3 are absorbed from the small intestine. Bile is essential for adequate absorption of vitamin D (see Chapter 46). The primary route of vitamin D3 excretion is the bile. Patients who have intestinal bypass surgery or have or inflammation of the small intestine may fail to absorb vitamin D sufficiently to maintain normal levels; hepatic or biliary dysfunction also may seriously impair vitamin D absorption. Absorbed vitamin D circulates in the blood in association with vitamin D binding protein. The vitamin disappears from plasma with a t1/2 of 20-30 h but is stored in fat depots for prolonged periods.
METABOLIC ACTIVATION. Vitamin D requires modification to become biologically active. The primary active metabolite is 1α,25-dihydroxy vitamin D (calcitriol), the product of 2 successive hydroxylations (see Figure 44–4).
25-Hydroxylation of Vitamin D., The initial hydroxylation occurs in the liver to generate 25-OH-cholecalciferol (25-OHD, or calcifediol) and 25-OH-ergocalciferol, respectively. 25-OHD is the major circulating form of vitamin D3; it has a biological t1/2 of 19 days, and normal steady-state concentrations are 15-50 ng/mL.
1α-Hydroxylation of 25-OHD., After production in the liver, 25-OHD enters the circulation and is carried by vitamin D–binding globulin. Final activation occurs primarily in thekidney, where the enzyme 1 α-hydroxylase in the proximal tubules converts 25-OHD to calcitriol. This process is highly regulated (Figure 44–5). Calcitriol controls 1 α-hydroxylase activity by a negative-feedback mechanism that involves a direct action on the kidney, as well as inhibition of PTH secretion. The plasma t1/2 of calcitriol is estimated at 3-5 days in humans.
Figure 44–5 Regulation of 1 α-hydroxylase activity. Changes in the plasma levels of PTH, Ca2+, and phospate modulate the hydroxylation of 25-OH vitamin D to the active form, 1,25-dihydroxyvitamin D. 25-OHD, 25-hydroxycholecalciferol; 1,25-(OH)2-D, calcitriol; PTH, parathyroid hormone.
PHYSIOLOGICAL FUNCTIONS AND MECHANISM OF ACTION. Calcitriol augments absorption and retention of Ca2+ and phosphate. Calcitriol acts to maintain normal concentrations of Ca2+ and phosphate in plasma by facilitating their absorption in the small intestine, by interacting with PTH to enhance their mobilization from bone, and by decreasing their renal excretion. The actions of calcitriol are mediated by binding to cytosolic VDRs within target cells, and the receptor–hormone complex translocates to the nucleus and interacts with DNA to modify gene transcription. The VDR belongs to the steroid and thyroid hormone receptor superfamily. Calcitriol also exerts nongenomic effects.
Calcium is absorbed predominantly in the duodenum. In the absence of calcitriol, GI calcium absorption is inefficient and involves passive diffusion via a paracellular pathway. Ca2+ absorption is potently augmented by calcitriol. It is likely that calcitriol enhances all 3 steps involved in intestinal Ca2+ absorption: entry across mucosal membranes (possibly involving TRPV6 Ca2+ channels), diffusion through the enterocytes, and active extrusion across serosal plasma membranes. Calcitriol upregulates the synthesis of calbindin-D9K, calbindin-D28K, and the serosal plasma membrane Ca2+–ATPase. Calbindin-D9K enhances the extrusion of Ca2+ by the Ca2+–ATPase; the precise function of calbindin-D28K is unsettled.
The primary role of calcitriol is to stimulate intestinal absorption of Ca2+, which, in turn, indirectly promotes bone mineralization. Thus, PTH and calcitriol act independently to enhance bone resorption. Osteoblasts, the cells responsible for bone formation, express the VDR, and calcitriol induces their production of several proteins, including osteocalcin, a vitamin K–dependent protein that contains γ-carboxyglutamic acid residues, and interleukin-1 (IL-1), a lymphokine that promotes bone resorption. Thus, the current view is that calcitriol is a bone-mobilizing hormone but not a bone-forming hormone. Osteoporosis is a disease in which osteoclast responsiveness to calcitriol or other bone-resorbing agents is profoundly impaired, leading to deficient bone resorption.
Other Effects of Calcitriol., Effects of calcitriol extend well beyond calcium homeostasis. Receptors for calcitriol are distributed widely throughout the body. Calcitriol affects maturation and differentiation of mononuclear cells and influences cytokine production and immune function. Calcitriol inhibits epidermal proliferation and promotes epidermal differentiation and therefore is a potential treatment for psoriasis vulgaris (see Chapter 65).
Calcitonin is a hypocalcemic hormone whose actions generally oppose those of PTH. The thyroid parafollicular C cells produce and secrete calcitonin. Calcitonin is the most potent peptide inhibitor of osteoclast-mediated bone resorption and helps to protect the skeleton during periods of “calcium stress,” such as growth, pregnancy, and lactation.
Regulation of Secretion. Calcitonin is a single-chain peptide of 32 amino acids with a disulfide bridge linking cys1 and cys7. The biosynthesis and secretion of calcitonin are regulated by the plasma [Ca2+]. Calcitonin secretion increases when plasma Ca2+ is high and decreases when plasma Ca2+ is low. The circulating concentrations of calcitonin are low, normally <15 and 10 pg/mL for males and females, respectively. The circulating t1/2 of calcitonin is ~10 min. Abnormally elevated levels of calcitonin are characteristic of thyroid C cell hyperplasia and medullary thyroid carcinoma. Differential splicing of the 6 exons of the calcitonin gene leads to tissue-specific production of calcitonin, katacalcin, and calcitonin gene-related peptide (CGRP).
Mechanism of Action. The calcitonin receptor (CTR), a GPCR that couples to multiple G proteins, mediates calcitonin’s actions. The hypocalcemic and hypophosphatemic effects of calcitonin are caused predominantly by direct inhibition of osteoclastic bone resorption. CGRP and the closely related peptide adrenomedullin are potent endogenous vasodilators.
FIBROBLAST GROWTH FACTOR 23 AND KLOTHO
Fibroblast growth factor 23 (FGF23), a protein of 251 amino acids, is produced primarily by bone cells including osteoblasts, osteocytes, and lining cells. FGF23 is secreted in response to dietary phosphorus load; its main function is the promotion of urinary phosphate excretion and the suppression of active vitamin D production by the kidney. Klotho is a membrane protein that serves as an essential cofactor in the transduction of FGF23 signaling. Exogenous FGF23 administration reduces serum Pi and calcitriol synthesis. Although no clinical agents based on FGF23 have yet been developed, bioactive fragments or FGF23 inhibitors might become useful in counterbalancing the hyperphosphatemic actions of vitamin D therapy.
The skeleton is the primary structural support for the body and also provides a protected environment for hematopoiesis. It contains both a large mineralized matrix and a highly active cellular compartment.
BONE MASS. Bone mineral density (BMD) and fracture risk in later years reflect the maximal bone mineral content at skeletal maturity (peak bone mass) and the subsequent rate of bone loss. Major increases in bone mass, accounting for ~60% of final adult levels, occur during adolescence, mainly during years of highest growth velocity. Inheritance accounts for much of the variance in bone acquisition; other factors include circulating estrogen and androgens, physical activity, and dietary calcium. Bone mass peaks during the third decade, remains stable until age 50, and then declines progressively. In women, loss of estrogen at menopause accelerates the rate of bone loss. Primary regulators of adult bone mass include physical activity, reproductive endocrine status, and calcium intake. Optimal maintenance of BMD requires sufficiency in all 3 areas, and deficiency of one is not compensated by excessive attention to another.
BONE REMODELING. Once new bone is laid down, it is subject to a continuous process of breakdown and renewal called remodeling, by which bone mass is adjusted throughout adult life. Remodeling is carried out by myriad independent “bone remodeling units” throughout the skeleton. In response to physical or biochemical signals, recruitment of marrow precursor cells to the bone surface results in their fusion into the characteristic multinucleated osteoclasts that resorb, or excavate, a cavity into the bone. Osteoclast production is regulated by osteoblast-derived cytokines (e.g., IL-1 and IL-6). One important mechanism is the receptor for activating NF-nB (RANK) and its natural ligand, RANK ligand (RANKL; previously called osteoclast differentiation factor). On binding to RANK, RANKL induces osteoclast formation (Figure 44–6). RANKL initiates the activation of mature osteoclasts, as well as the differentiation of osteoclast precursors. Osteoblasts produce osteoprotegerin (OPG), which acts as a decoy ligand that inhibits osteoclast production by competing effectively with RANKL for binding to RANK. Under conditions favoring increased bone resorption, such as estrogen deprivation, OPG is suppressed, RANKL binds to RANK, and osteoclast production increases. When estrogen sufficiency is reestablished, OPG increases and competes effectively with RANKL for binding to RANK.
Figure 44–6 Receptor for activating NF-κB ligand (RANKL) and osteoclast formation. RANKL, acting on RANK, promotes osteoclast formation and subsequent resorption of bone matrix. Osteoprotegerin (OPG) binds to RANKL, reducing its binding to RANK and thereby inhibiting osteoclast differentiation.
The resorption phase is followed by invasion of preosteoblasts into the base of the resorption cavity. These cells become osteoblasts and elaborate new bone matrix constituents that help form osteoid. Once the newly formed osteoid reaches a thickness of ~20 µm, mineralization begins. A complete remodeling cycle normally requires ~6 months. Small bone deficits persist on completion of each cycle, reflecting inefficient remodeling dynamics. Consequently, lifelong accumulation of remodeling deficits underlies the well-documented phenomenon of age-related bone loss, a process that begins shortly after growth stops. Alterations in remodeling activity represent the final pathway through which diverse stimuli, such as dietary sufficiency, exercise, hormones, and drugs, affect bone balance.
DISORDERS OF MINERAL HOMEOSTASIS AND BONE
ABNORMAL CALCIUM METABOLISM
HYPERCALCEMIA. In an outpatient setting, the most common cause of hypercalcemia is primary hyperparathyroidism, which results from hypersecretion of PTH by 1 or more parathyroid glands. Symptoms and signs of primary hyperparathyroidism include fatigue, exhaustion, weakness, polydipsia, polyuria, joint pain, bone pain, constipation, depression, anorexia, nausea, heartburn, nephrolithiasis, and hematuria. This condition frequently is accompanied by significant hypophosphatemia owing to the effects of PTH in diminishing renal tubular phosphate reabsorption.
Vitamin D excess may cause hypercalcemia if sufficient 25-OHD is present to stimulate intestinal Ca2+ hyperabsorption, leading to hypercalcemia and suppressing PTH and 1,25-dihydroxyvitamin D levels. Measurement of 25-OHD is diagnostic. Serum assays for PTH, PTHrP, and 25-OH- and 1,25-(OH)2D permit accurate diagnosis in the great majority of cases.
Hypercalcemia in hospitalized patients is caused most often by a systemic malignancy, either with or without bony metastasis. PTH-related protein (PTHrP) is a primitive, highly conserved protein that may be abnormally expressed in malignant tissue. The PTHrP interacts with the PTH-1 receptor in target tissues, thereby causing the hypercalcemia and hypophosphatemia seen in humoral hypercalcemia of malignancy. In some patients with lymphomas, hypercalcemia results from overproduction of 1,25-dihydroxyvitamin D by the tumor cells owing to expression of 1 α-hydroxylase.
HYPOCALCEMIA. Combined deprivation of Ca2+ and vitamin D, as observed with malabsorption states, readily promotes hypocalcemia. When caused by malabsorption, hypocalcemia is accompanied by low concentrations of phosphate, total plasma proteins, and magnesium. Mild hypocalcemia (i.e., serum Ca2+ in the range of 8-8.5 mg/dL [2-2.1 mM]), is usually asymptomatic. Patients exhibit greater symptoms if the hypocalcemia develops acutely.
Symptoms of hypocalcemia include tetany and related phenomena such as paresthesias, increased neuromuscular excitability, laryngospasm, muscle cramps, and tonic-clonic convulsions. In chronichypoparathyroidism, ectodermal changes (e.g., consisting of loss of hair, grooved and brittle fingernails, defects of dental enamel, and cataracts) occur. Psychiatric symptoms such as emotional lability, anxiety, depression, and delusions often are present. Hypoparathyroidis m is most often a consequence of thyroid or neck surgery but also may be due to genetic or autoimmune disorders.Pseudohypoparathyroidism is a diverse family of hypocalcemic and hyperphosphatemic disorders. Pseudohypoparathyroidism results from resistance to PTH; this resistance is due to mutations in Gsα (GNAS1), which normally mediates hormone-induced adenylyl cyclase activation. Multiple hormonal abnormalities have been associated with the GNAS1 mutation, but none is as severe as the deficient response to PTH.
DISTURBED PHOSPHATE METABOLISM
Dietary inadequacy very rarely causes phosphate depletion. Sustained use of antacids, however, can severely limit phosphate absorption and result in clinical phosphate depletion, manifest as malaise, muscle weakness, and osteomalacia (see Chapter 45). Osteomalacia is characterized by undermineralized bone matrix and may occur when sustained phosphate depletion is caused by inhibiting its absorption in the GI tract (as with aluminum-containing antacids) or by excess renal excretion owing to PTH action. Hyperphosphatemia occurs commonly in chronic renal failure. The increased phosphate level reduces the serum Ca2+ concentration, which, in turn, activates the parathyroid gland calcium-sensing receptor, stimulates PTH secretion, and exacerbates the hyperphosphatemia. The FDA recently approved therapeutic use of the calcium-sensing receptor agonist cinacalcet to suppress PTH secretion.
DISORDERS OF VITAMIN D
HYPERVITAMINOSIS D. The acute or long-term administration of excessive amounts of vitamin D or enhanced responsiveness to normal amounts of the vitamin leads to derangements in calcium metabolism. In adults, hypervitaminosis D results from overtreatment of hypoparathyroidism and from faddist use of excessive doses. The amount of vitamin D necessary to cause hypervitaminosis varies widely. As a rough approximation, continued daily ingestion of >50,000 units may result in poisoning. The initial signs and symptoms of vitamin D toxicity are those associated with hypercalcemia.
Vitamin D Deficiency. Vitamin D deficiency results in inadequate absorption of Ca2+ and phosphate. The consequent decrease of plasma Ca2+ concentration stimulates PTH secretion, which acts to restore plasma Ca2+ at the expense of bone. Plasma concentrations of phosphate remain subnormal because of the phosphaturic effect of increased circulating PTH. In children, the result is a failure to mineralize newly formed bone and cartilage matrix, causing the defect in growth known as rickets. In adults, vitamin D deficiency results in osteomalacia, a disease characterized by generalized accumulation of undermineralized bone matrix. Muscle weakness, particularly of large proximal muscles, is typical and may reflect both hypophosphatemia and inadequate vitamin D action on muscle. Gross deformity of bone occurs only in advanced stages of the disease. Circulating 25-OHD concentrations <8 ng/mL are highly predictive of osteomalacia.
METABOLIC RICKETS AND OSTEOMALACIA. These disorders are characterized by abnormalities in calcitriol synthesis or response. Variants include hypophosphatemic vitamin D–resistant rickets, vitamin D–dependent rickets, hereditary 1,25-dihydroxyvitamin D resistance, and renal osteodystrophy (renal rickets). See Chapter 44 of the 12th edition of the parent text for details.
Osteoporosis is a condition of low bone mass and microarchitectural disruption that results in fractures with minimal trauma. Many women (30-50%) and men (15-30%) suffer a fracture related to osteoporosis. Characteristic sites of fracture include vertebral bodies, the distal radius, and the proximal femur, but osteoporotic individuals have generalized skeletal fragility, and fractures at sites such as ribs and long bones also are common. Fracture risk increases exponentially with age, and spine and hip fractures are associated with reduced survival.
Osteoporosis can be categorized as primary or secondary. Primary osteoporosis represents 2 different conditions: type I osteoporosis, characterized by loss of trabecular bone owing to estrogen lack at menopause, and type II osteoporosis, characterized by loss of cortical and trabecular bone in men and women due to long-term remodeling inefficiency, dietary inadequacy, and activation of the parathyroid axis with age. Secondary osteoporosis is due to systemic illness or medications such as glucocorticoids or phenytoin. The most successful approach to secondary osteoporosis is prompt resolution of the underlying cause or drug discontinuation. Whether primary or secondary, osteoporosis is associated with characteristic disordered bone remodeling, so the same therapies can be used.
PAGET DISEASE. Paget disease is characterized by single or multiple sites of disordered bone remodeling. It affects up to 2-3% of the population >60 years of age. The primary pathologic abnormality is increased bone resorption followed by exuberant bone formation. However, the newly formed bone is disorganized and of poor quality, resulting in characteristic bowing, stress fractures, and arthritis of joints adjoining the involved bone. The altered bone structure can produce secondary problems, such as deafness, spinal cord compression, high-output cardiac failure, and pain. Malignant degeneration to osteogenic sarcoma is a rare but lethal complication of Paget disease.
RENAL OSTEODYSTROPHY. Bone disease is a frequent consequence of chronic renal failure and dialysis. Pathologically, lesions are typical of hyperparathyroidism (osteitis fibrosa), vitamin D deficiency (osteomalacia), or a mixture of both. The underlying pathophysiology reflects increased serum phosphate and decreased calcium, leading to the loss of bone.
PHARMACOLOGICAL TREATMENT OF DISORDERS OF MINERAL ION HOMEOSTASIS AND BONE METABOLISM
Hypercalcemia can be life threatening. Such patients frequently are severely dehydrated because hypercalcemia compromises renal concentrating mechanisms. Thus, fluid resuscitation with large volumes of isotonic saline must be early and aggressive (6-8 L/day). Agents that augment Ca2+ excretion, such as loop diuretics (see Chapter 25), may help to counteract the effect of plasma volume expansion by saline but are contraindicated until volume is repleted.
Corticosteroids administered at high doses (e.g., 40-80 mg/day of prednisone) may be useful when hypercalcemia results from sarcoidosis, lymphoma, or hypervitaminosis D (see Chapter 42). The response to steroid therapy is slow; from 1-2 weeks may be required before plasma Ca2+ concentration falls. Calcitonin (CALCIMAR, MIACALCIN) may be useful in managing hypercalcemia. Reduction in Ca2+ can be rapid, although “escape” from the hormone commonly occurs within several days. The recommended starting dose is 4 units/kg of body weight administered subcutaneously every 12 h; if there is no response within 1-2 days, the dose may be increased to a maximum of 8 units/kg every 12 h. If the response after 2 more days still is unsatisfactory, the dose may be increased to a maximum of 8 units/kg every 6 h. Calcitonin can lower serum calcium by 1-2 mg/dL.
Intravenous bisphosphonates (pamidronate, zoledronate) have proven very effective in the management of hypercalcemia (see below for discussion of bisphosphonates). These agents potently inhibit osteoclastic bone resorption. Pamidronate (AREDIA) is given as an intravenous infusion of 60-90 mg over 4-24 h. With pamidronate, resolution of hypercalcemia occurs over several days, and the effect usually persists for several weeks. Zoledronate (ZOMETA) has superseded pamidronate because of its more rapid normalization of serum Ca2+ and longer duration of action.
Plicamycin (mithramycin, MITHRACIN) is a cytotoxic antibiotic that also decreases plasma Ca2+ concentrations by inhibiting bone resorption. Reduction in plasma Ca2+ concentrations occurs within 24-48 h when a relatively low dose of this agent is given (15-25 µg/kg of body weight) to minimize the high systemic toxicity of the drug; indeed, its toxicity generally precludes its use.
Once the hypercalcemic crisis has resolved or in patients with milder calcium elevations, long-term therapy is initiated. Parathyroidectomy remains the only definitive treatment for primary hyperparathyroidism. As described later, a calcium mimetic that stimulates the CaSR is a promising new therapy for hyperparathyroidism. Therapy of hypercalcemia of malignancy ideally is directed at the underlying cancer. When this is not possible, parenteral bisphosphonates often will maintain Ca2+ levels within an acceptable range.
HYPOCALCEMIA AND OTHER THERAPEUTIC USES OF CALCIUM
Hypoparathyroidism is treated primarily with vitamin D and dietary supplementation with Ca2+ as various calcium salts. Calcium chloride (CaCl2•2H2O) contains 27% Ca2+; it is valuable in the treatment of hypocalcemic tetany and laryngospasm. The salt is given intravenously and must never be injected into tissues. Injections of calcium chloride are accompanied by peripheral vasodilation and a cutaneous burning sensation. The salt usually is given intravenously in a concentration of 10% (equivalent to 1.36 mEq Ca2+/mL). The rate of injection should be slow (not >1 mL/min) to prevent cardiac arrhythmias from a high concentration of Ca2+. The injection may induce a moderate fall in blood pressure owing to vasodilation. Calcium gluceptate injection (a 22% solution; 18 mg or 0.9 mEq of Ca2+/mL) is administered intravenously at a dose of 5-20 mL for the treatment of severe hypocalcemic tetany. Calcium gluconate injection (a 10% solution; 9.3 mg of Ca2+/mL) given intravenously is the treatment of choice for severe hypocalcemic tetany. The intramuscular route should not be employed because abscess formation at the injection site may result.
Calcium carbonate and calcium acetate are used to restrict phosphate absorption in patients with chronic renal failure and oxalate absorption in patients with inflammatory bowel disease. Acute administration of Ca2+ may be lifesaving in patients with extreme hyperkalemia (serum K+ > 7 mEq/L). Calcium gluconate (10-30 mL of a 10% solution) can reverse some of the cardiotoxic effects of hyperkalemia. Additional FDA-approved uses of Ca2+ include intravenous treatment for black widow spider envenomation and management of magnesium toxicity.
THERAPEUTIC USES OF VITAMIN D
CLINICAL FORMS OF VITAMIN D. Calcitriol (1,25-dihydroxycholecalciferol; CALCIJEX, ROCALTROL) is available for oral administration or injection. Several derivatives of vitamin D are also used therapeutically.
Doxercalciferol (1α-hydroxyvitamin D2, HECTOROL), a prodrug that first must be activated by hepatic 25-hydroxylation, is approved for use in treating secondary hyperparathyroidism. Dihydrotachysterol (DHT, ROXANE) is a reduced form of vitamin D2. In the liver, DHT is converted to its active form, 25-OH dihydrotachysterol. DHT is effective in mobilizing bone mineral at high doses; it therefore can be used to maintain plasma Ca2+ in hypoparathyroidism. DHT is well absorbed from the GI tract and maximally increases serum Ca2+ concentration after 2 weeks of daily administration. The hypercalcemic effects typically persist for 2 weeks but can last for up to 1 month. DHT is available for oral administration in doses ranging from 0.2-1 mg/day (average 0.6 mg/day).
Ergocalciferol (calciferol, DRISDOL) is pure vitamin D2. It is available for oral, intramuscular, or intravenous administration. Ergocalciferol is indicated for the prevention of vitamin D deficiency and the treatment of familial hypophosphatemia, hypoparathyroidism, and vitamin D–resistant rickets type II, typically in doses of 50,000-200,000 units/day in conjunction with calcium supplements. 1α-Hydroxycholecalciferol (1-OHD3, alphacalcidol; ONE-ALPHA) is a synthetic vitamin D3 derivative that is already hydroxylated in the 1α position and is rapidly hydroxylated by 25-hydroxylase to form 1,25-(OH)2D3. It is equal to calcitriol in assays for stimulation of intestinal absorption of Ca2+ and bone mineralization and does not require renal activation. It is available in the U.S. for experimental purposes.
ANALOGS OF CALCITRIOL. Several vitamin D analogs suppress PTH secretion by the parathyroid glands but have less or negligible hypercalcemic activity. They therefore offer a safer and more effective means of controlling secondary hyperparathyroidism.
Calcipotriol (calcipotriene) is a synthetic derivative of calcitriol with a modified side chain. Calcipotriol is <1% as active as calcitriol in regulating Ca2+ metabolism. Calcipotriol has been studied extensively as a treatment for psoriasis (see Chapter 65).
Paricalcitol (1,25-dihydroxy-19-norvitamin D2, ZEMPLAR) is a synthetic calcitriol derivative that lacks the exocyclic C19 and has a vitamin D2 rather than vitamin D3 side chain (see Figure 44–4). It reduces serum PTH levels without producing hypercalcemia or altering serum phosphorus. Paricalcitol administered intravenously is FDA-approved for treating secondary hyperparathyroidism in patients with chronic renal failure.
22-Oxacalcitriol (1,25-dihydroxy-22-oxavitamin D3, OCT, maxacalcitol, OXAROL) differs from calcitriol only in the substitution of C-22 with an O atom. Oxacalcitriol has a low affinity for vitamin D–binding protein; thus, more of the drug circulates in the free (unbound) form and is metabolized more rapidly than calcitriol with a consequent shorter t1/2. Oxacalcitriol is a potent suppressor of PTH gene expression and shows very limited activity on intestine and bone. It is a useful compound in patients with overproduction of PTH in chronic renal failure.
THERAPEUTIC INDICATIONS FOR VITAMIN D
The major therapeutic uses of vitamin D are:
• Prophylaxis and cure of nutritional rickets
• Treatment of metabolic rickets and osteomalacia, particularly in the setting of chronic renal failure
• Treatment of hypoparathyroidism
• Prevention and treatment of osteoporosis
• Dietary supplementation
NUTRITIONAL RICKETS. Nutritional rickets results from inadequate exposure to sunlight or deficiency of dietary vitamin D. The incidence of this condition in the U.S. is now increasing. Infants and children receiving adequate amounts of vitamin D–fortified food do not require additional vitamin D; however, breast-fed infants or those fed unfortified formula should receive 400 units of vitamin D daily as a supplement (see Table 44–1), usually administered with vitamin A, for which purpose a number of balanced vitamin A and D preparations are available. Because the fetus acquires >85% of its calcium stores during the third trimester, premature infants are especially susceptible to rickets and may require supplemental vitamin D. Treatment of fully developed rickets requires a larger dose of vitamin D than that used prophylactically. One thousand units daily will normalize plasma Ca2+ and phosphate concentrations in ~10 days, with radiographic evidence of healing within ~3 weeks. However, a larger dose of 3000–4000 units daily often is prescribed for more rapid healing, particularly when respiration is compromised by severe thoracic rickets.
TREATMENT OF OSTEOMALACIA AND RENAL OSTEODYSTROPHY. Osteomalacia, distinguished by undermineralization of bone matrix, occurs commonly during sustained phosphate depletion. Patients with chronic renal disease are at risk for developing osteomalacia but also may develop a complex bone disease called renal osteodystrophy. In this setting, bone metabolism is stimulated by an increase in PTH and by a delay in bone mineralization that is due to decreased renal synthesis of calcitriol. In renal osteodystrophy, low bone mineral density may be accompanied by high-turnover bone lesions typically seen in patients with uncontrolled hyperparathyroidism or by low bone remodeling activity seen in patients with adynamic bone disease. The therapeutic approach to the patient with renal osteodystrophy depends on its specific type. In high-turnover (hyperparathyroid) or mixed high-turnover disease with deficient mineralization, dietary phosphate restriction, generally in combination with a phosphate binder, is recommended. Calcium-containing phosphate binders along with calcitriol administration may contribute to oversuppression of PTH secretion and likewise result in adynamic bone disease and an increased incidence of vascular calcification.
Highly effective non-calcium-containing phosphate binders have been developed. Sevelamer hydrochloride (RENAGEL), a nonabsorbable phosphate-binding polymer, effectively lowers serum phosphate concentration in hemodialysis patients. Sevelamer is modestly water soluble and only trace amounts are absorbed from the GI tract. Side effects of sevelamer include vomiting, nausea, diarrhea, and dyspepsia. Sevelamer does not affect the bioavailability of digoxin, warfarin, enalapril, or metoprolol. Lanthanum carbonate (FOSRENOL) is a poorly permeable trivalent cation that is useful in treating the hyperphosphatemia associated with renal osteodystrophy.
HYPOPARATHYROIDISM. Vitamin D and its analogs are a mainstay of the therapy of hypoparathyroidism. DHT has a faster onset, shorter duration of action, and a greater effect on bone mobilization than does vitamin D and traditionally has been a preferred agent. Calcitriol may be preferred for temporary treatment of hypocalcemia while awaiting effects of a slower-acting form of vitamin D.
PREVENTION AND TREATMENT OF OSTEOPOROSIS. This is described separately, earlier in the chapter.
DIETARY SUPPLEMENTATION. See Table 44–1.
ADVERSE EFFECTS OF VITAMIN D THERAPY
The primary toxicity associated with calcitriol reflects its potent effect to increase intestinal absorption of Ca2+ and phosphate, along with the potential to mobilize osseous Ca2+ and phosphate. Hypercalcemia, with or without hyperphosphatemia, commonly complicates calcitriol therapy and may limit its use at doses that effectively suppress PTH secretion. Noncalcemic vitamin D analogs provide alternative interventions, although they do not obviate the need to monitor serum Ca2+ and phosphorus concentrations. Hypervitaminosis D is treated by immediate withdrawal of the vitamin, a low-calcium diet, administration of glucocorticoids, and vigorous fluid support; forced saline diuresis with loop diuretics is also useful. With this regimen, the plasma Ca2+ concentration falls to normal, and Ca2+ in soft tissue tends to be mobilized. Conspicuous improvement in renal function occurs unless renal damage has been severe.
DIAGNOSTIC USE. Calcitonin is a sensitive and specific marker for the presence of medullary thyroid carcinoma (MTC), a neuroendocrine malignancy originating in thyroid parafollicular C cells.
THERAPEUTIC USE. Calcitonin lowers plasma Ca2+ and phosphate concentrations in patients with hypercalcemia. Although calcitonin is effective for up to 6 h in the initial treatment of hypercalcemia, patients become refractory after a few days. This is likely due to receptor downregulation. Use of calcitonin does not substitute for aggressive fluid resuscitation, and the bisphosphonates are the preferred agents. Calcitonin is effective in disorders of increased skeletal remodeling, such as Paget disease, and in some patients with osteoporosis. For Paget disease, calcitonin generally is administered by subcutaneous injection because intranasal delivery is relatively ineffective owing to limited bioavailability. After initial therapy at 100 units/day, the dose typically is reduced to 50 units 3 times a week. Side effects of calcitonin include nausea, hand swelling, urticaria, and, rarely, intestinal cramping.
Bisphosphonates are analogs of pyrophosphate that contain 2 phosphonate groups attached to a geminal (central) carbon that replaces the oxygen in pyrophosphate (Figure 44–7). These agents form a 3-dimensional structure capable of chelating divalent cations such as Ca2+ and have a strong affinity for bone, targeting especially bone surfaces undergoing remodeling.
Figure 44–7 Pyrophosphate and bisphosphonates. The substituents (R1 and R2) on the central carbon of the bisphosphonate parent structure are shown in blue.
Bisphosphonates are used extensively in conditions characterized by osteoclast-mediated bone resorption, including osteoporosis, steroid-induced osteoporosis, Paget disease, tumor-associated osteolysis, breast and prostate cancer, and hypercalcemia. Calcium supplements, antacids, food or medications containing divalent cations, such as iron, may interfere with intestinal absorption of bisphosphonates. Recent evidence suggests that second- and third-generation bisphosphonates also may be effective anticancer drugs.
Bisphosphonates act by direct inhibition of bone resorption. First-generation bisphosphonates contain minimally modified side chains (medronate, clodronate, and etidronate) or possess a chlorophenol group (tiludronate) and are the least potent agents. Second-generation aminobisphosphonates (e.g., alendronate and pamidronate) contain a nitrogen group in the side chain and are 10-100 times more potent than first-generation compounds. Third-generation bisphosphonates (e.g., risedronate and zoledronate) contain a nitrogen atom within a heterocyclic ring and are up to 10,000 times more potent than first-generation agents.
Bisphosphonates concentrate at sites of active remodeling, remain in the matrix until the bone is remodeled, and then are released in the acid environment of the resorption lacunae and induce apoptosis in osteoclasts. Although bisphosphonates prevent hydroxyapatite dissolution, their antiresorptive action is due to direct inhibitory effects on osteoclasts rather than strictly physiochemical effects. The antiresorptive activity apparently involves 2 primary mechanisms: osteoclast apoptosis and inhibition of components of the cholesterol biosynthetic pathway.
AVAILABLE BISPHOSPHONATES. Etidronate sodium (DIDRONEL) is used for treatment of Paget disease. Etidronate has been supplanted largely by pamidronate and zoledronate for treating hypercalcemia. Pamidronate (AREDIA; available in the U.S. only for parenteral administration) is approved for management of hypercalcemia and for prevention of bone loss in breast cancer and multiple myeloma, and also is effective in other skeletal disorders. For treatment of hypercalcemia, pamidronate may be given as an intravenous infusion of 60-90 mg over 4-24 h. Several newer bisphosphonates have been approved for treatment of Paget disease. These include tiludronate (SKELID), alendronate (FOSAMAX), and risedronate (ACTONEL). Tiludronate standard dosing is 400 mg/day orally for 3 months. Tiludronate in recommended doses does not interfere with bone mineralization, unlike etidronate. Zoledronate (ZOMETA) is approved for treating Paget disease; administered as a single 5-mg infusion, zoledronate decreases bone turnover markers for 6 months with no loss of therapeutic effect. Zoledronate is widely used for prevention of osteoporosis in prostate and breast cancer patients receiving hormonal therapy. It reduces both vertebral and nonvertebral fractures. A 4-mg formulation is available for intravenous treatment of hypercalcemia of malignancy, multiple myeloma, or bone metastasis resulting from solid tumors. The potent bisphosphonate ibandronate (BONIVA) is approved for the prevention and treatment of postmenopausal osteoporosis. The recommended oral dose is 2.5 mg daily or 150 mg once monthly.
For patients in whom oral bisphosphonates cause severe esophageal distress, intravenous zoledronate (RECLAST) or ibandronate offer skeletal protection without causing adverse GI effects. For treatment of osteoporosis, ibandronate (3 mg) is given intravenously every 3 months. Zoledronate is the first bisphosphonate to be approved from once-yearly intravenous treatment of osteoporosis (5 mg annually).
ADME. All oral bisphosphonates are very poorly absorbed from the intestine and have remarkably limited bioavailability (<1% [alendronate, risedronate] to 6% [etidronate, tiludronate]). Hence, these drugs should be administered with a full glass of water following an overnight fast and at least 30 min before breakfast. Oral bisphosphonates have not been used widely in children or adolescents because of uncertainty of long-term effects of bisphosphonates on the growing skeleton. Bisphosphonates are excreted primarily by the kidneys and are not recommended for patients with a creatinine clearance of <30 mL/min.
ADVERSE EFFECTS. Oral bisphosphonates can cause heartburn, esophageal irritation, or esophagitis. Other GI side effects include abdominal pain and diarrhea. Symptoms often abate when patients take the medication after an overnight fast, with tap or filtered water (not mineral water), and remain upright. Patients with active upper GI disease should not be given oral bisphosphonates. Serious osteonecrosis of the jaw is associated with use of bisphosphonates. Initial parenteral infusion of pamidronate may cause skin flushing, flu-like symptoms, muscle and joint aches and pains, nausea and vomiting, abdominal discomfort and diarrhea (or constipation) but mainly when given in higher concentrations or at faster rates than those recommended. These symptoms are short lived and generally do not recur with subsequent administration. Zoledronate can cause severe hypocalcemia and has been associated with renal toxicity, deterioration of renal function, and potential renal failure. Infusion of zoledronate should be given over at least 15 min, and the dose should be 4 mg; patients should have standard laboratory and clinical parameters of renal function assessed prior to treatment and periodically after treatment to monitor for deterioration in renal function.
OTHER THERAPEUTIC USES
Postmenopausal Osteoporosis. Much interest is focused on the role of bisphosphonates in the treatment of osteoporosis. Clinical trials show that treatment is associated with increased bone mineral density and protection against fracture.
Cancer. Bisphosphonates may also have direct antitumor action by inhibiting oncogene activation and through their anti-angiogenic effects. Randomized clinical trials of bisphosphonates in patients with breast cancer suggest that these agents delay or prevent development of metastases as a component of endocrine adjuvant therapy.
Continuous administration of PTH or high-circulating PTH levels achieved in primary hyperparathyroidism causes bone demineralization and osteopenia. However, intermittent PTH administration promotes bone growth. Synthetic human 34-amino-acid amino-terminal PTH fragment [hPTH(1-34), teriparatide (FORTEO)] is approved for use in treating severe osteoporosis.
ADME. Pharmacokinetics and systemic actions of teriparatide on mineral metabolism are the same as for PTH. Teriparatide is administered by once-daily subcutaneous injection of 20 µg into the thigh or abdomen. Serum PTH concentrations peak at 30 min after the injection and are undetectable within 3 h, whereas the serum Ca2+ concentration peaks at 4-6 h after administration. Teriparatide bioavailability averages 95%; clearance averages 62 L/h in women and 94 L/h in men. The serum t1/2 of teriparatide is ~1 h when administered subcutaneously versus 5 min when administered intravenously. The elimination of PTH(1-34) and full-length PTH proceeds by nonspecific enzymatic mechanisms in the liver, followed by renal excretion.
CLINICAL EFFECTS. In postmenopausal women with osteoporosis, teriparatide increases BMD and reduces the risk of vertebral and nonvertebral fractures. Candidates for teriparatide treatment include women who have a history of osteoporotic fracture, who have multiple risk factors for fracture, or who failed or are intolerant of previous osteoporosis therapy. Men with primary or hypogonadal osteoporosis are also candidates for treatment with teriparatide.
ADVERSE EFFECTS. Adverse effects include exacerbation of nephrolithiasis and elevation of serum uric acid levels. Teriparatide use should be limited to no more than 2 years and should not be used in patients who are at increased baseline risk for osteosarcoma (including those with Paget disease of bone, unexplained elevations of alkaline phosphatase, open epiphyses, or prior radiation therapy involving the skeleton). A tumor registry-based analysis of the occurrence of osteosarcoma in teriparatide-treated patients is ongoing; cases of osteosarcoma associated with the drug should be reported to the FDA.
CALCIUM SENSOR MIMETICS: CINACALCET
Calcimimetics are drugs that mimic the stimulatory effect of Ca2+ on the calcium-sensing receptor (CaSR) to inhibit PTH secretion by the parathyroid glands. By enhancing the sensitivity of the CaSR to extracellular Ca2+, calcimimetics lower the concentration of Ca2+ at which PTH secretion is suppressed. Inorganic di- and trivalent cations, along with polycations such as spermine, aminoglycosides (e.g., streptomycin, gentamicin, and neomycin) and polybasic amino acids (e.g., polylysine) are full agonists and are referred to a type I calcimimetics. Phenylalkylamine derivatives that are allosteric CaSR modulators that require the presence of Ca2+ or other full agonists to enhance the sensitivity of activation without altering the maximal response are designated type II calcimimetics. Cinacalcet (SENSIPAR) is approved for the treatment of secondary hyperparathyroidism. Cinacalcet lowers serum PTH levels in patients with normal or reduced renal function.
ADME. Cinacalcet exhibits first-order absorption, with maximal serum concentrations achieved 2-6 h after oral administration. Maximal effects on serum PTH occur 2–4 h after administration. Cinacalcet has a t1/2 of 30-40 h and is eliminated primarily by renal excretion (85%); the drug is also metabolized by multiple hepatic cytochromes, including CYPs 3A4, 2D6, and 1A2.
Cinacalcet is available in 30-, 60-, and 90-mg tablets. The recommended starting dose for treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis is 30 mg once daily, with a maximum of 180 mg/day. For treatment of parathyroid carcinoma, a starting dose of 30 mg twice daily is recommended, with a maximum of 90 mg 4 times daily. The starting dose is titrated upward every 2-4 weeks to maintain the PTH level between 150 and 300 pg/mL (secondary hyperparathyroidism) or to normalize serum calcium (parathyroid carcinoma).
ADVERSE REACTIONS. The principal adverse event with cinacalcet is hypocalcemia. Thus, the drug should not be used if the initial serum [Ca2+] is <8.4 mg/dL; serum Ca2+ and phosphorus concentrations should be measured within 1 week, and PTH should be measured within 4 weeks after initiating therapy or after changing dosage. Seizure threshold is lowered by significant reductions in serum Ca2+, so patients with a history of seizure disorders should be monitored especially closely. Finally, adynamic bone disease may develop if the PTH level is <100 pg/mL, and the drug should be discontinued or the dose decreased if the PTH level falls below 150 pg/mL.
DRUG INTERACTIONS. Potential drug interactions can be anticipated with drugs that interfere with Ca2+ homeostasis or that hinder cinacalcet absorption. Potentially interfering drugs may include vitamin D analogs, phosphate binders, bisphosphonates, calcitonin, glucocorticoids, gallium, and cisplatin. Caution is recommended when cinacalcet is coadministered with inhibitors of CYP3A4 (e.g., ketoconazole, erythromycin, or itraconazole), CYP2D6 (many β adrenergic receptor blockers, flecainide, vinblastine, and most tricyclic antidepressants), and many other drugs.
INTEGRATED APPROACH TO PREVENTION AND TREATMENT OF OSTEOPOROSIS
Osteoporosis is a major and growing public health problem in developed nations. Approximately 50% women and 25% of men >50 years of age will experience an osteoporosis-related fracture. However, important reductions in fracture risk can be achieved with appropriate lifelong attention to prevention (muscle strengthening exercise; avoiding smoking and excessive alcohol use). Attention to nutritional status (i.e., increased dietary calcium or calcium and/or vitamin D supplements) also may be required. Pharmacological agents used to manage osteoporosis act by decreasing the rate of bone resorption and thereby slowing the rate of bone loss (antiresorptive therapy) or by promoting bone formation (anabolic therapy). Because bone remodeling is a coupled process, antiresorptive drugs ultimately decrease the rate of bone formation and therefore do not promote substantial gains in BMD.
Pharmacological treatment of osteoporosis is aimed at restoring bone strength and preventing fractures. Antiresorptive drugs such as the bisphosphonates, estrogen, or the selective estrogen receptor modulator (SERM) raloxifene, and, to some extent, calcitonin inhibit osteoclast-mediated bone loss, thereby reducing bone turnover. Although the administration of estrogen to women at menopause is a powerful intervention to preserve bone and protect against fracture, the detrimental effects of hormone-replacement therapy (HRT) have mandated a major reexamination on treatment options (see later andChapter 40). In addition to antiresorptive agents, the FDA has approved the biologically active PTH fragment PTH(1–34) (teriparatide, FORTEO) for use in treating postmenopausal women with osteoporosis and to increase bone mass in men with primary or hypogonadal osteoporosis.
Bisphosphonates. Bisphosphonates are the most frequently used drugs for the prevention and treatment of osteoporosis. Second- and third-generation oral bisphosphonates alendronate and risedronate have sufficient potency to suppress bone resorption at doses that do not inhibit mineralization. Alendronate (FOSAMAX), risedronate (ACTONEL), and ibandronate (BONIVA) are approved for prevention and treatment of osteoporosis and for the treatment of glucocorticoid-associated osteoporosis.
Denosumab. RANKL binds to its cognate receptor RANK on the surface of precursor and mature osteoclasts, and stimulates these cells to mature and resorb bone. OPG, which competes with RANK for binding to RANKL, is the physiological inhibitor of RANKL. Denosumab is an investigational human monoclonal antibody that binds with high affinity to RANKL, mimicking the effect of OPG, and thereby reducing the binding of RANKL to RANK. Denosumab blocks osteoclast formation and activation. It increases BMD and decreases bone turnover markers when given subcutaneously, 60 mg once every 6 months.
Selective Estradiol Receptor Modulators (SERMs). Raloxifene (EVISTA) acts as an estrogen agonist on bone and liver, is inactive on the uterus, and acts as an anti-estrogen on the breast (see Chapter 40). In postmenopausal women, raloxifene stabilizes and modestly increases BMD and has been shown to reduce the risk of vertebral compression fracture. Raloxifene is approved for both the prevention and treatment of osteoporosis. The major drawback of raloxifene is that it can worsen vasomotor symptoms.
Estrogen. Postmenopausal status or estrogen deficiency at any age significantly increases a patient’s risk for osteoporosis and fractures. Likewise, overwhelming evidence supports the positive impact of estrogen replacement on the conservation of bone and protection against osteoporotic fracture after menopause (see Chapter 40). Since the outcome of the Women’s Health Initiative (WHI) studies has indicated significantly increased risks of heart disease and breast cancer, the consensus now is to reserve HRT only for the short-term relief of vasomotor symptoms associated with menopause.
Calcium. The rationale for using supplemental calcium to protect bone varies with time of life. For preteens and adolescents, adequate substrate calcium is required for bone accretion. Higher calcium intake during the third decade of life is positively related to the final phase of bone acquisition. There is controversy about the role of calcium during the early years after menopause, when the primary basis for bone loss is estrogen withdrawal. In elderly subjects, supplemental calcium suppresses bone turnover and improves BMD.
Vitamin D and Its Analogs. Modest supplementation with vitamin D (400-800 IU/day) may improve intestinal Ca2+ absorption, suppress bone remodeling, and improve BMD in individuals with marginal or deficient vitamin D status. A prospective study found that neither dietary calcium nor vitamin D intake was of major importance for the primary prevention of osteoporotic fractures in women. However, supplemental vitamin D in combination with calcium reduced fracture incidence in multiple trials. The use of calcitriol to treat osteoporosis is distinct from ensuring vitamin D nutritional adequacy. Here, the rationale is to suppress parathyroid function directly and reduce bone turnover. Calcitriol and the polar vitamin D metabolite 1e-hydroxycholecalciferol are used frequently in Japan and other countries, but experience in the U.S. has been mixed.
Calcitonin. Calcitonin inhibits osteoclastic bone resorption and modestly increases bone mass in patients with osteoporosis, most prominently in patients with high intrinsic rates of bone turnover. Calcitonin nasal spray (200 units/day) reportedly reduces the incidence of vertebral compression fractures by ~40% in osteoporotic women.
Thiazide Diuretics. Although not strictly antiresorptive, thiazides reduce urinary Ca2+ excretion and constrain bone loss in patients with hypercalciuria. Hydrochlorothiazide, 25 mg once or twice daily, may reduce urinary Ca2+ excretion substantially. Effective doses of thiazides for reducing urinary Ca2+ excretion generally are lower than those necessary for blood pressure control (see Chapter 25).
Teriparatide. Teriparatide (FORTEO) is the only agent currently available that increases new bone formation. It is FDA-approved for treatment of osteoporosis for up to 2 years in both men and postmenopausal women at high risk for fractures. Teriparatide significantly decreased the incidence of vertebral (4-5% vs. 14%) and nonvertebral fractures (3% vs. 6%) compared to placebo in a prospective, randomized control study. Teriparatide increases predominantly trabecular bone at the lumbar spine and femoral neck; it has less significant effects at cortical sites. Teriparatide is approved at the 20 µg dose, administered once daily by subcutaneous injection in the thigh or abdominal wall. The most common adverse effects associated with teriparatide include injection-site pain, nausea, headaches, leg cramps, and dizziness.
OSTEOPOROSIS. Because teriparatide stimulates bone formation, whereas bisphosphonates reduce bone resorption, it was predicted that therapy combining the 2 would enhance the effect on BMD more than treatment with either one alone. However, addition of alendronate to PTH treatment provided no additional benefit for BMD and reduced the anabolic effect of PTH in both women and men. Sequential treatment with PTH(1-84) followed by alendronate increased vertebral BMD to a greater degree than alendronate or estrogen alone.
PAGET DISEASE. Although most patients with Paget disease require no treatment, factors such as severe pain, neural compression, progressive deformity, hypercalcemia, high-output congestive heart failure, and repeated fracture risk are considered indications for treatment. Bisphosphonates and calcitonin decrease the elevated biochemical markers of bone turnover, such as plasma alkaline phosphatase activity and urinary excretion of hydroxyproline. An initial course of bisphosphonate typically is given once daily or once weekly for 6 months. With treatment, most patients experience a decrease in bone pain over several weeks. Such treatment may induce long-lasting remission. If symptoms recur, additional courses of therapy can be effective. Optimal therapy for Paget disease varies among patients. Bisphosphonates are the standard therapy. Intravenous pamidronate induces long-term remission following a single infusion. Zoledronate seems to exhibit greater response rates and a longer median duration of complete response. Compared with calcitonin, bisphosphonates have the advantage of oral administration, lower cost, lack of antigenicity, and generally fewer side effects.
Fluoride is discussed because of its effects on dentition and bone and its toxic properties.
ADME. Fluoride is obtained from the ingestion of plants and water, with most absorption taking place in the intestine. A second route of absorption is through the lungs, and inhalation of fluoride present in dusts and gases constitutes the major route of industrial exposure. Fluoride is distributed widely in organs and tissues but is concentrated in bone and teeth, and the skeletal burden is related to intake and age. Bone deposition reflects skeletal turnover; growing bone shows greater deposition than mature bone. The kidneys are the major site of fluoride excretion. Small amounts of fluoride also appear in sweat, milk, and intestinal secretions.
PHARMACOLOGICAL ACTIONS AND USES. Because it is concentrated in the bone, the radionuclide 18F has been used in skeletal imaging. Sodium fluoride enhances osteoblast activity and increases bone volume. These effects may be bimodal, with low doses stimulating and higher doses suppressing osteoblasts. However, the apparent effects of fluoride in osteoporosis are slight compared with those achieved with PTH or others. Fluoride can inhibit several enzyme systems and diminish tissue respiration and anaerobic glycolysis.
Fluoride and Dental Caries. Supplementation of water fluoride content to 1.0 ppm is a safe and practical intervention that substantially reduces the incidence of caries in permanent teeth. There are partial benefits for children who begin drinking fluoridated water at any age; however, optimal benefits are obtained at ages before permanent teeth erupt. Topical application of fluoride solutions by dental personnel appears to be effective on newly erupted teeth and can reduce the incidence of caries by 30-40%. Dietary fluoride supplements should be considered for children <12 years of age whose drinking water contains <0.7 ppm fluoride. Adequate incorporation of fluoride into teeth hardens the outer layers of enamel and increases resistance to demineralization. The fluoride salts usually employed in dentifrices are sodium fluoride and stannous fluoride. Sodium fluoride also is available in a variety of preparations for oral and topical use.
Regulation of the fluoride concentration of community water supplies periodically encounters vocal opposition, including allegations of putative adverse health consequences of fluoridated water. Careful examination of these issues indicates that cancer and all-cause mortalities do not differ significantly between communities with fluoridated and nonfluoridated water.
ACUTE POISONING. Acute fluoride poisoning usually results from accidental ingestion of fluoride-containing insecticides or rodenticides. Initial symptoms (salivation, nausea, abdominal pain, vomiting, and diarrhea) are secondary to the local action of fluoride on the intestinal mucosa. Systemic symptoms are varied and severe: increased irritability of the central nervous system consistent with the Ca2+-binding effect of fluoride and the resulting hypocalcemia; hypotension, presumably owing to central vasomotor depression as well as direct cardiotoxicity; and stimulation and then depression of respiration. Death can result from respiratory paralysis or cardiac failure. The lethal dose of sodium fluoride for humans is ~5 g, although there is considerable variation. Treatment includes the intravenous administration of glucose in saline and gastric lavage with lime water (0.15% calcium hydroxide solution) or other Ca2+ salts to precipitate the fluoride. Calcium gluconate is given intravenously for tetany; urine volume is kept high with vigorous fluid resuscitation.
CHRONIC POISONING. In humans, the major manifestations of chronic ingestion of excessive fluoride are osteosclerosis and mottled enamel. Osteosclerosis is characterized by increased bone density secondary both to elevated osteoblastic activity and to the replacement of hydroxyapatite by the denser fluoroapatite. The degree of skeletal involvement varies from changes that are barely detectable radiologically to marked cortical thickening of long bones, numerous exostoses scattered throughout the skeleton, and calcification of ligaments, tendons, and muscle attachments. In its severest form, it is a disabling and crippling disease.
Mottled enamel, or dental fluorosis, was first described >60 years ago. In very mild mottling, small, opaque, paper-white areas are scattered irregularly over the tooth surface. In severe cases, discrete or confluent, deep brown- to black-stained pits give the tooth a corroded appearance. Mottled enamel results from a partial failure of the enamel-forming ameloblasts to elaborate and lay down enamel. Mottling is one of the first visible signs of excess fluoride intake during childhood. Continuous use of water containing ~1 ppm of fluoride may result in very mild mottling in 10% of children; at 4-6 ppm the incidence approaches 100%, with a marked increase in severity. Severe dental fluorosis formerly occurred in regions where local water supplies had a very high fluoride content (e.g., Pompeii, Italy, and Pike’s Peak, Colorado). Current regulations in the U.S. require lowering the fluoride content of the water supply or providing an alternative source of acceptable drinking water for affected communities. Sustained consumption of water with a fluoride content of 4 mg/L (4 ppm) is associated with deficits in cortical bone mass and increased rates of bone loss over time.