Drugs That Affect Bone Mineral Homeostasis: Introduction
Calcium and phosphorus, the 2 major elements of bone, are crucial not only for the mechanical strength of the skeleton but also for the normal function of many other cells in the body. Accordingly, a complex regulatory mechanism has evolved to tightly regulate calcium and phosphate homeostasis. Parathyroid hormone (PTH) and vitamin D are primary regulators (Figure 42-1), whereas calcitonin, glucocorticoids, and estrogens play secondary roles. These hormones or drugs that mimic or suppress their actions are used in the treatment of bone mineral disorders (eg, osteoporosis, rickets, osteomalacia, Paget's disease), as are several nonhormonal agents.
FIGURE 42-1
Effects of active metabolites of vitamin D (D), parathyroid hormone (PTH), calcitonin (CT), and fibroblast growth factor 23 (FGF23) on calcium and phosphorus homeostasis. Active metabolites of vitamin D increase absorption of calcium from both gut and bone, whereas PTH increases reabsorption from bone. Vitamin D metabolites and PTH both reduce urinary excretion ofcalcium. In animals with vitamin D deficiency, active metabolites of vitamin D produce a net increase in bone mineralization by increasing the availability of serum calcium and phosphate.
(Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 41-1.)
High-Yield Terms to Learn
Hyperparathyroidism A condition of PTH excess characterized by hypercalcemia, bone pain, cognitive abnormalities, and renal stones. Primary disease results from parathyroid gland dysfunction. Secondary disease most commonly results from chronic kidney disease Osteoblast Bone cell that promotes bone formation Osteoclast Bone cell that promotes bone resorption Osteomalacia A condition of abnormal mineralization of adult bone secondary to nutritional deficiency of vitamin D or inherited defects in the formation or action of active vitamin D metabolites Osteoporosis Abnormal loss of bone with increased risk of fractures, spinal deformities, and loss of stature; remaining bone is histologically normal Paget's disease A bone disorder, of unknown origin, characterized by excessive bone destruction and disorganized repair. Complications include skeletal deformity, musculoskeletal pain, kidney stones, and organ dysfunction secondary to pressure from bony overgrowth Rickets The same as osteomalacia, but it occurs in the growing skeleton RANK ligand An osteoblast-derived growth factor that stimulates osteoclast activity and osteoclast precursor differentiation
Hormonal Regulators of Bone Mineral Homeostasis
Parathyroid Hormone
Parathyroid hormone (PTH), an 84-amino-acid peptide, acts on membrane G-protein-coupled receptors to increase cyclic adenosine monophosphate (cAMP) in bone and renal tubular cells. In the kidney, PTH inhibits calcium excretion, promotes phosphate excretion, and stimulates the production of active vitamin D metabolites (Figure 42-1, Table 42-1). In bone, PTH promotes bone turnover by increasing the activity of both osteoblasts and osteoclasts (Figure 42-2B). Osteoclast activation is not a direct effect and instead results from PTH stimulation of osteoblast formation of RANK ligand (RANKL), a member of the tumor necrosis factor (TNF) cytokine family that stimulates the activity of mature osteoclasts and the differentiation of osteoclast precursors.
TABLE 42-1 Actions of PTH and active vitamin D metabolites on intestine, kidney, and bone.
Organ PTH Active Vitamin D Metabolites Intestine Indirectly increases calcium and phosphate absorption by increasing vitamin D metabolites Increased calcium and phosphate absorption Kidney Decreased calcium excretion, increased phosphate excretion Increased resorption of calcium and phosphate but usually net increase in urinary calcium due to effects in GI tract and bone Bone Calcium and phosphate resorption increased by continuous high concentrations. Low intermittent doses increase bone formation Direct effect is increased calcium and phosphate resorption; indirect effect is promoting mineralization by increasing the availability of calcium and phosphate Net effect on serum levels Serum calcium increased, serum phosphate decreased Serum calcium and phosphate both increased
Reproduced and modified, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009.
FIGURE 42-2
Hormonal interactions controlling bone mineral homeostasis. (A) The 1,25-dihydroxyvitamin D that is produced by the kidney under control of parathyroid hormone (PTH) and fibroblast growth hormone 23 (FGF23) stimulates intestinal uptake of calcium and phosphate, and, in those with vitamin D deficiency, promotes bone formation. Calcitonin inhibits resorption from bone, whereas PTH stimulates bone resorption. Extracellular calcium and 1,25-dihydroxyvitamin D inhibit PTH production. (B) Both PTH and 1,25-dihydroxyvitamin D regulate bone formation and resorption. This is accomplished by their activation of precursor differentiation and by stimulation of osteoblast production of signaling factors, including RANK ligand (RANKL), macrophage colony-stimulating factor (MCSF), and osteoprotegerin.
(Reproduced and modified, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 42-2.)
At the continuous high concentrations seen in hyperparathyroidism, the net effect of elevated PTH is increased bone resorption, hypercalcemia, and hyperphosphatemia. However, low intermittent doses of PTH produce a net increase in bone formation; this is the basis of the use of teriparatide , a recombinant truncated form of PTH, for parenteral treatment of osteoporosis.
The synthesis and secretion of PTH is primarily regulated by the serum concentration of free ionized calcium; a drop in free ionized calcium stimulates PTH release. Active metabolites of vitamin D play a secondary role in regulating PTH secretion by inhibiting PTH synthesis (Figure 42-2A).
Vitamin D
Vitamin D, a fat-soluble vitamin (Figure 42-3), can be synthesized in the skin from 7-dehydrocholesterol under the influence of ultraviolet light or absorbed from the diet in the natural form (vitamin D3 , cholecalciferol ) or the plant form (vitamin D2 , ergocalciferol ). Active metabolites are formed in the liver (25-hydroxyvitamin D or calcifediol) and kidney (1,25-dihydroxyvitamin D or calcitriol plus other metabolites). Renal synthesis of active vitamin D metabolites is stimulated by PTH and by fibroblast growth factor 23 (FGF23), a factor produced by osteoblasts and osteoclasts. Renal synthesis of 1,25-dihydroxyvitamin D2 is inhibited by phosphate and vitamin D metabolites (Figure 41-2). The action of vitamin D metabolites is mediated by activation of 1 or possibly a family of nuclear receptors that regulate gene expression.
FIGURE 42-3
Conversion of 7-dehydroxycholsterol to vitamin D3 and metabolism of vitamin D 3 to 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and to 24,25-dihydroxyvitamin D3 (24,25(OH)2D3). The inset shows the side chain for ergosterol. Ergosterol undergoes similar transformation to vitamin D2 (ergocalciferol), which, in turn is metabolized to 1,25-dihydroxyvitamin D2 and 24,25-dihydroxyvitamin D2. In humans, corresponding D2 and D3 have equivalent effects and potency. They are therefore referred to in the text without a subscript.
(Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 42-3.)
Active vitamin D metabolites cause a net increase in serum concentrations of calcium and phosphate by increasing intestinal absorption and bone resorption and decreasing renal excretion (Figure 42-1, Table 42-1). Because their effect in the gastrointestinal (GI) tract and bone is greater than their effect in the kidney, they also increase urinary calcium. Active vitamin D metabolites are required for normal mineralization of bone; deficiencies cause rickets in growing children and adolescents and osteomalacia in adults. Vitamin D metabolites inhibit PTH secretion directly and indirectly, by increasing serum calcium.
Vitamin D, vitamin D metabolites, and synthetic derivatives are used to treat deficiency states, including nutritional deficiency, intestinal osteodystrophy, chronic kidney or liver disease, hypoparathyroidism, and nephrotic syndrome. They are also used, in combination with calcium supplementation, to prevent and treat osteoporosis in older women and men. Topical formulations are used in psoriasis, a hyperproliferative skin disorder. The 2 forms of vitamin D—cholecalciferol and ergocalciferol—are available as oral supplements and are commonly added to dairy products and other foods. In patients with conditions that impair vitamin D activation (chronic kidney disease, liver disease, hypoparathyroidism), an active form of vitamin D such as calcitriol is required. In the treatment of secondary hyperparathyroidism associated with chronic kidney disease, calcitriol reduces PTH levels, corrects hypocalcemia, and improves bone disease, but it can also result in hypercalcemia and hypercalciuria through direct effects on intestinal, bone, and renal handling of calcium and phosphate. Several forms of active vitamin D that selectively inhibit PTH formation while posing less risk of hypercalcemia have been developed. 1
-Hydroxyvitamin D2 ( doxercalciferol ) is a prodrug that is converted in the liver to 1,25-dihyroxyvitamin D, whereas 19-nor-1,25-dihydroxyvitamin D2 ( paricalcitol ) and calcipotriene(calcipotriol) are analogs of calcitriol. All cause less hypercalcemia and, in patients with normal renal function, less hypercalciuria than calcitriol. Oral and parenteral doxercalciferol and oral paricalcitol are approved for treatment of secondary hyperparathyroidism in patients with chronic kidney disease. Calcipotriene (calcipotriol) is approved for topical treatment of psoriasis. These and other analogs are being investigated for use in various malignancies and inflammatory disorders.
The primary toxicity caused by chronic overdose with vitamin D or its active metabolites is hypercalcemia, hyperphosphatemia, and hypercalciuria.
Calcitonin
Calcitonin, a peptide hormone secreted by the thyroid gland, decreases serum calcium and phosphate by inhibiting bone resorption and inhibiting renal excretion of these minerals (Figure 42-1). Bone formation is not impaired initially, but ultimately it is reduced. The hormone has been used in conditions in which an acute reduction of serum calcium is needed (eg, Paget's disease and hypercalcemia). Calcitonin is approved for treatment of osteoporosis and has been shown to increase bone mass and to reduce spine fractures. However, it is not as effective as teriparatide or bisphosphonates. Although human calcitonin is available, salmon calcitonin is most often selected for clinical use because of its longer half-life and greater potency. Calcitonin is administered by injection or as a nasal spray.
Estrogens
Estrogens and selective estrogen receptor modulators (SERMs; eg, raloxifene ) can prevent or delay bone loss in postmenopausal women (see Chapter 40). Their action involves the inhibition of PTH-stimulated bone resorption (Figure 42-2B).
Glucocorticoids
The glucocorticoids (Chapter 39) inhibit bone mineral maintenance. As a result, chronic systemic use of these drugs is a common cause of osteoporosis in adults. However, these hormones are useful in the intermediate-term treatment of hypercalcemia.
Skill Keeper: Diuretics and Calcium
(See Chapter 15)
The kidney is a key regulator of serum calcium concentrations. Several diuretics affect the kidney's handling of filtered calcium.
1. Which 2 classes of diuretics have opposite effects on calcium elimination?
2. What mechanisms are responsible for their opposing effects?
3. What is the clinical importance of these effects?
The Skill Keeper Answers appear at the end of the chapter.
Nonhormonal Agents
Bisphosphonates
The bisphosphonates (alendronate, etidronate, ibandronate, pamidronate, risedronate, tiludronate, and zoledronic acid) are short-chain organic polyphosphate compounds that reduce both the resorption and the formation of bone by an action on the basic hydroxyapatite crystal structure. The bisphosphonates have other complex cellular effects, including effects on vitamin D production and calcium absorption from the GI tract, and direct effects on osteoclasts, including inhibition of farnesyl pyrophosphate synthase, an enzyme that appears to play a critical role in osteoclast survival. Bisphosphonates are used to manage the hypercalcemia associated with some malignancies and to treat Paget's disease. Chronic bisphosphonate therapy is used commonly to prevent and treat all forms of osteoporosis. It has been shown to increase bone density and reduce fractures.
Pamidronate, zoledronic acid, or etidronate are available for parenteral treatment of hypercalcemia associated with Paget's disease and malignancies. Etidronate and the other bisphosphonates listed above are available as oral medications. Oral bioavailability of bisphosphonates is low (<10%), and food impairs their absorption. Bisphosphonate treatment of osteoporosis is accomplished with daily oral dosing (alendronate, risedronate, ibandronate); weekly oral dosing (alendronate, risedronate); monthly oral dosing (ibandronate); quarterly injection dosing (ibandronate); or annual infusions (zoledronate). The primary toxicity of the low oral bisphosphonate doses used for osteoporosis is gastric and esophageal irritation. To reduce esophageal irritation, patients are advised to take the drugs with large quantities of water and avoid situations that permit esophageal reflux. The higher doses of bisphosphonates used to treat hypercalcemia have been associated with renal impairment and osteonecrosis of the jaw.
Calcimimetics
Cinacalcet lowers PTH by activating the calcium-sensing receptor in the parathyroid gland. It is used for oral treatment of secondary hyperparathyroidism in chronic kidney disease and for the treatment of hypercalcemia in patients with parathyroid carcinoma. Its toxicities include hypocalcemia and adynamic bone disease, a condition of profoundly decreased bone cell activity.
Fluoride
Appropriate concentrations of fluoride ion in drinking water or as an additive in toothpaste have a well-documented ability to reduce dental caries. Chronic exposure to the ion, especially in high concentrations, may increase new bone synthesis. It is not clear, however, whether this new bone is normal in strength. Clinical trials of fluoride in patients with osteoporosis have not demonstrated a reduction in fractures. Acute toxicity of fluoride (usually caused by ingestion of rat poison) is manifested by gastrointestinal and neurologic symptoms.
Other Drugs with Effects on Serum Calcium and Phosphate
Strontium ranelate, an organic ion bound to 2 atoms of strontium, promotes osteoclast apoptosis and increases concentrations of bone formation markers; it is used in Europe for treatment of osteoporosis. Gallium nitrate is effective in managing the hypercalcemia associated with some malignancies and possibly Paget's disease. It acts by inhibiting bone resorption. To prevent nephrotoxicity, patients need to be well hydrated and to have good renal output. The antibiotic plicamycin (mithramycin) has been used to reduce serum calcium and bone resorption in Paget's disease and hypercalcemia. Because of the risk of serious toxicity (eg, thrombocytopenia, hemorrhage, hepatic and renal damage), plicamycin is mainly restricted to short-term treatment of serious hypercalcemia. Several diuretics, most notably thiazide diuretics and furosemide, can affect serum and urinary calcium levels (see this chapter's Skill Keeper). The phosphate-binding gel sevelamer is used in combination with calcium supplements and dietary phosphate restriction to treat hyperphosphatemia, a common complication of renal failure, hypoparathyroidism, and vitamin D intoxication.
Skill Keeper Answers: Diuretics and Calcium
(See Chapter 15)
1. Loop diuretics (eg, furosemide) and thiazide diuretics have opposite effects on urine calcium concentrations; loop diuretics increase urine concentrations of calcium, whereas the thiazides decrease urine calcium.
2. Loop diuretics inhibit the Na+/K+/2Cl-cotransporter in apical membranes of the thick ascending limb of the loop of Henle (see Figure 15-3). By disrupting the positive lumen-positive potential that normally serves as the driving force for resorption of Mg2+and Ca2+ , loop diuretics inhibit Mg2+ and Ca2+ resorption, leaving more Mg2+ and Ca2+ in the urine and less in the blood. In the distal convoluted tubule where thiazides act, Ca2+ is actively resorbed through the concerted action of an apical Ca2+ channel and a basolateral Na+/Ca2+ exchanger (see Figure 15-4). The system is under control of the PTH. When thiazides inhibit the Na+/Cl- transporter in cells that line the distal convoluted tubule, they lower the intracellular concentration of sodium and thereby enhance the Na+/Ca2+ exchange that occurs on the basolateral surface. This, in turn, creates a greater driving force for passage of Ca2+through the apical membrane calcium channels. The net effect is enhanced resorption of calcium.
3. In patients with hypercalcemia, treatment with a loop diuretic plus saline promotes calcium excretion and lowers serum calcium. In patients with intact regulatory function, increases in calcium resorption promoted by thiazides have minor impact on serum calcium because of buffering in bone and gut. However, thiazides can unmask hypercalcemia in patients with diseases that disrupt normal calcium regulation (eg, hyperparathyroidism, sarcoidosis, carcinoma). Thiazide diuretics are also used for treatment of persons who are prone to kidney stone formation as a result of idiopathic hypercalciuria. In such persons, it is crucial that primary hyperparathyroidism is ruled out before thiazide treatment is initiated.
Checklist
When you complete this chapter, you should be able to:
Identify the major and minor endogenous regulators of bone mineral homeostasis.
Sketch the pathway and sites of formation of 1,25-dihydroxyvitamin D.
Compare and contrast the clinical uses and effects of the major forms of vitamin D and its active metabolites.
Describe the major effects of PTH and vitamin D derivatives on the intestine, the kidney, and bone.
Describe the agents used in the treatment of hypercalcemia and the agents used in the treatment of osteoporosis.
Recall the effects of adrenal and gonadal steroids on bone structure and the actions of diuretics on serum calcium levels.
Drug Summary Table: Drugs Affecting Bone Mineral Metabolism
Subclass Mechanism of Action Clinical Applications Pharmacokinetics Toxicities, Drug Interactions Vitamin D, metabolites, analogs Cholecalciferol, ergocalciferol Regulates gene transcription via the vitamin D receptor to produce the effects detailed in Table 42-1 Vitamin D deficiency Oral administration Hypercalcemia, hyperphosphatemia, hypercalciuria Calcitriol: Used for management of secondary hyperparathyroidism in patients with chronic kidney disease and for management of hypocalcemia in patients with hypoparathyroidism Doxercalciferol (1-hydroxyvitamin D3): Used for management of secondary hyperparathyroidism in patients with chronic kidney disease Paricalcitol: An analog of calcitriol used for management of secondary hyperparathyroidism in patients with chronic kidney disease Calcipotriene: An analog of calcitriol approved for psoriasis Bisphosphonates Alendronate Suppresses the activity of osteoclasts and inhibits bone resorptions Osteoporosis, Paget's disease Oral administration daily or weekly Adynamic bone, esophageal irritation, osteonecrosis of the jaw (rare) Risedronate, ibandronate, pamidronate, zoledronate: Similar to alendronate Parathyroid hormone (PTH) analog Teriparatide Acts through PTH receptors to produce a net increase in bone formation Osteoporosis Subcutaneous injection Hypercalcemia, hypercalciuria; osteosarcoma in experimental animals Calcitonin Calcitonin Acts through calcitonin receptors to inhibit bone resorption Osteoporosis Subcutaneous injection or intranasal Rhinitis with the nasal spray Selective estrogen-receptor modulator (see Chapter 40) Raloxifene Estrogen agonist effect in bone; estrogen antagonist effects in breast and endometrium Osteoporosis in postmenopausal women Oral administration Hot flushes, thromboembolism Calcimimetic Cinacalcet Activates the calcium-sensing receptor Hyperparathyroidism Oral administration Nausea, hypocalcemia, adynamic bone