Case Study

A 65-year-old man is referred to you from his primary care physician (PCP) for evaluation and management of possible osteoporosis. He saw his PCP for evaluation of low back pain. X-rays of the spine showed some degenerative changes in the lumbar spine plus several wedge deformities in the thoracic spine. The patient is a long-time smoker (up to two packs per day) and has two to four glasses of wine with dinner, more on the weekends. He has chronic bronchitis, presumably from smoking and has been treated many times with oral prednisone for exacerbations of bronchitis. He is currently on 10 mg/d prednisone. Examination shows kyphosis of the thoracic spine, with some tenderness to fist percussion over the thoracic spine. The DEXA (dual-energy x-ray absorptiometry) measurement of the lumbar spine is "within the normal limits," but the radiologist noted that the reading may be misleading because of the degenerative changes. The hip measurement shows a T score (number of standard deviations that the patient's measured bone density is from normal young adult bone density) in the femoral neck of –2.2. What further workup should be considered, and what therapy should be initiated?

Basic Pharmacology

Calcium and phosphate, the major mineral constituents of bone, are also two of the most important minerals for general cellular function. Accordingly, the body has evolved a complex set of mechanisms by which calcium and phosphate homeostasis are carefully maintained (Figure 42–1). Approximately 98% of the 1–2 kg of calcium and 85% of the 1 kg of phosphorus in the human adult are found in bone, the principal reservoir for these minerals. These functions are dynamic, with constant remodeling of bone and ready exchange of bone mineral with that in the extracellular fluid. Bone also serves as the principal structural support for the body and provides the space for hematopoiesis. Thus, abnormalities in bone mineral homeostasis can lead not only to a wide variety of cellular dysfunctions (eg, tetany, coma, muscle weakness) but also to disturbances in structural support of the body (eg, osteoporosis with fractures) and loss of hematopoietic capacity (eg, infantile osteopetrosis).

Calcium and phosphate enter the body from the intestine. The average American diet provides 600–1000 mg of calcium per day, of which approximately 100–250 mg is absorbed. This figure represents net absorption, because both absorption (principally in the duodenum and upper jejunum) and secretion (principally in the ileum) occur. The amount of phosphorus in the American diet is about the same as that of calcium. However, the efficiency of absorption (principally in the jejunum) is greater, ranging from 70% to 90%, depending on intake. In the steady state, renal excretion of calcium and phosphate balances intestinal absorption. In general, over 98% of filtered calcium and 85% of filtered phosphate is reabsorbed by the kidney. The movement of calcium and phosphate across the intestinal and renal epithelia is closely regulated. Intrinsic disease of the intestine (eg, nontropical sprue) or kidney (eg, chronic renal failure) disrupts bone mineral homeostasis.

Three hormones serve as the principal regulators of calcium and phosphate homeostasis: parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), and the steroid vitamin D (Figure 42–2). Vitamin D is a prohormone rather than a true hormone, because it must be further metabolized to gain biologic activity. PTH stimulates the production of the active metabolite of vitamin D, 1,25(OH)₂D. 1,25(OH)₂D, on the other hand, suppresses the production of PTH. 1,25(OH)₂D stimulates the intestinal absorption of calcium and phosphate. 1,25(OH)₂D and PTH promote both bone formation and resorption in part by stimulating the proliferation and differentiation of osteoblasts and osteoclasts. Both PTH and 1,25(OH)₂D enhance renal retention of calcium, but PTH promotes renal phosphate excretion. FGF23 is a recently discovered hormone that stimulates renal phosphate excretion and inhibits renal production of 1,25(OH)₂D. Other hormones—calcitonin, prolactin, growth hormone, insulin, thyroid hormone, glucocorticoids, and sex steroids—influence calcium and phosphate homeostasis under certain physiologic circumstances and can be considered secondary regulators. Deficiency or excess of these secondary regulators within a physiologic range does not produce the disturbance of calcium and phosphate homeostasis that is observed in situations of deficiency or excess of PTH, FGF23, and vitamin D. However, certain of these secondary regulators—especially calcitonin, glucocorticoids, and estrogens—are useful therapeutically and are discussed in subsequent sections.

In addition to these hormonal regulators, calcium and phosphate themselves, other ions such as sodium and fluoride, and a variety of drugs (bisphosphonates, plicamycin, and diuretics) also alter calcium and phosphate homeostasis.

Principal Hormonal Regulators of Bone Mineral Homeostasis

Parathyroid Hormone

Parathyroid hormone (PTH) is a single-chain peptide hormone composed of 84 amino acids. It is produced in the para-thyroid gland in a precursor form of 115 amino acids, the remaining 31 amino terminal amino acids being cleaved off before secretion. Within the gland is a calcium-sensitive protease capable of cleaving the intact hormone into fragments. Biologic activity resides in the amino terminal region such that synthetic PTH 1-34 is fully active. Loss of the first two amino terminal amino acids eliminates most biologic activity.

The metabolic clearance of intact PTH is rapid, with a half-time of disappearance measured in minutes. Most of the clearance occurs in the liver and kidney. The biologically inactive carboxyl terminal fragments produced during metabolism of the intact hormone have a much lower clearance, especially in current renal failure. This accounts in part for the very high PTH values often observed in the past in patients with renal failure when measured by radioimmunoassays directed against the carboxyl terminal region of the molecule. However, most PTH assays in current use measure the intact hormone by a double antibody method, so that this circumstance is less frequently encountered in clinical practice. PTH regulates calcium and phosphate flux across cellular membranes in bone and kidney, resulting in increased serum calcium and decreased serum phosphate. In bone, PTH increases the activity and number of osteoclasts, the cells responsible for bone resorption. However, this stimulation of osteoclasts is not a direct effect. Rather, PTH acts on the osteoblast (the bone-forming cell) to induce a membrane-bound protein called RANK ligand (RANKL). This factor acts on osteoclasts and osteoclast precursors to increase both the numbers and the activity of osteoclasts. This action increases bone turnover or bone remodeling, a specific sequence of cellular events initiated by osteoclastic bone resorption and followed by osteoblastic bone formation. Although both bone resorption and bone formation are enhanced by PTH, the net effect of excess PTH is to increase bone resorption. However, PTH in low and intermittent doses increases bone formation without first stimulating bone resorption. This action may be indirect, involving other growth factors such as insulin-like growth factor 1 (IGF-1). This has led to the recent approval of recombinant PTH 1-34 (teriparatide) for the treatment of osteoporosis. In the kidney, PTH increases the ability of the nephron to reabsorb calcium and magnesium but reduces its ability to reabsorb phosphate, amino acids, bicarbonate, sodium, chloride, and sulfate. Another important action of PTH on the kidney is its stimulation of 1,25-dihydroxyvitamin D (1,25[OH]₂D) production.

Vitamin D

Vitamin D is a secosteroid produced in the skin from 7-dehydrocholesterol under the influence of ultraviolet radiation. Vitamin D is also found in certain foods and is used to supplement dairy products. Both the natural form (vitamin D3, cholecalciferol) and the plant-derived form (vitamin D2, ergocalciferol) are present in the diet. These forms differ in that ergocalciferol contains a double bond (C_22–23) and an additional methyl group in the side chain (Figure 42–3). In humans, this difference apparently is of limited physiologic consequence (although ergocalciferol is less potent), and the following comments apply equally well to both forms of vitamin D.

Vitamin D is a prohormone that serves as precursor to a number of biologically active metabolites (Figure 42–3). Vitamin D is first hydroxylated in the liver to form 25-hydroxyvitamin D (25[OH]D). This metabolite is further converted in the kidney to a number of other forms, the best studied of which are 1,25-dihydroxyvitamin D (1,25[OH]₂D) and 24,25-dihydroxyvitamin D (24,25[OH]₂D). Of the natural metabolites, only vitamin D and 1,25(OH)₂D (as calcitriol) are available for clinical use (Table 42–1). Moreover, a number of analogs of 1,25(OH)₂D are being synthesized to extend the usefulness of this metabolite to a variety of nonclassic conditions. Calcipotriene (calcipotriol), for example, is being used to treat psoriasis, a hyperproliferative skin disorder. Doxercalciferol and paricalcitol have recently been approved for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease. Other analogs are being investigated for the treatment of various malignancies. The regulation of vitamin D metabolism is complex, involving calcium, phosphate, and a variety of hormones, the most important of which is PTH, which stimulates, and FGF23, which inhibits the production of 1,25(OH)₂D by the kidney.

Vitamin D and its metabolites circulate in plasma tightly bound to a carrier protein, the vitamin D-binding protein. This -globulin binds 25(OH)D and 24,25(OH)₂D with comparable high affinity and vitamin D and 1,25(OH)₂D with lower affinity. In normal subjects, the terminal half-life of injected calcifediol is 23 days, whereas in anephric subjects it is 42 days. The half-life of 24,25(OH)₂D is probably similar. Tracer studies with vitamin D have shown a rapid clearance from the blood. The liver appears to be the principal organ for clearance. Excess vitamin D is stored in adipose tissue. The metabolic clearance of calcitriol in humans indicates a rapid turnover, with a terminal half-life measured in hours. Several of the 1,25(OH)₂D analogs are bound poorly by the vitamin D-binding protein. As a result, their clearance is very rapid, with a terminal half-life of minutes. Such analogs have little of the hypercalcemic, hypercalciuric effects of calcitriol, an important aspect of their use for the management of conditions such as psoriasis and hyperparathyroidism.

The mechanism of action of the vitamin D metabolites remains under active investigation. However, calcitriol is well established as the most potent agent with respect to stimulation of intestinal calcium and phosphate transport and bone resorption. Calcitriol appears to act on the intestine both by induction of new protein synthesis (eg, calcium-binding protein and TRPV6, an intestinal calcium channel) and by modulation of calcium flux across the brush border and basolateral membranes by a means that does not require new protein synthesis. The molecular action of calcitriol on bone has received less attention. However, like PTH, calcitriol can induce RANK ligand in osteoblasts and proteins such as osteocalcin, which may regulate the mineralization process. The metabolites 25(OH)D and 24,25(OH)₂D are far less potent stimulators of intestinal calcium and phosphate transport or bone resorption. However, 25(OH)D appears to be more potent than 1,25(OH)₂D in stimulating renal reabsorption of calcium and phosphate and may be the major metabolite regulating calcium flux and contractility in muscle. Specific receptors for 1,25(OH)₂D exist in target tissues. However, the role and even the existence of separate receptors for 25(OH)D and 24,25(OH)₂D remain controversial.

The receptor for 1,25(OH)₂D exists in a wide variety of tissues—not just bone, gut, and kidney. In these "nonclassic" tissues, 1,25(OH)₂D exerts a number of actions including regulation of parathyroid hormone secretion from the parathyroid gland, insulin secretion from the pancreas, cytokine production by macrophages and T cells, and proliferation and differentiation of a large number of cells, including cancer cells. Thus, the clinical utility of 1,25(OH)₂D and its analogs is likely to expand.

Fibroblast Growth Factor 23

Fibroblast growth factor 23 (FGF23) is a single-chain protein with 251 amino acids including a 24-amino-acid leader sequence. It inhibits 1,25(OH)₂D3 production and phosphate reabsorption (via the sodium phosphate co-transporters NaPi 2a and 2c) in the kidney, leading to both hypophosphatemia and inappropriately low levels of circulating 1,25(OH)₂D₃. Although FGF23 was originally identified in certain mesenchymal tumors, osteoblasts and osteocytes in bone appear to be its primary site of production. However, other tissues can produce FGF23, though at lower levels. FGF23 requires O-glycosylation for its secretion, a glycosylation mediated by the glycosyl transferase GALNT3. Mutations in GALNT3 result in tumoral calcinosis with elevated phosphate and 1,25(OH)₂D₃. FGF23 is inactivated by cleavage at an RXXR site (amino acids 176–179) by subtilisin-like proprotein convertases such as furin. Mutations in this site lead to excess FGF23, the underlying problem in autosomal dominant hypophosphatemic rickets. The similar disease, X-linked hypophosphatemic rickets is due to mutations in PHEX, an endopeptidase, which initially was thought to cleave FGF23. However, this concept has been shown to be invalid. FGF23 binds to the FGF receptors 1 and IIIc in the presence of the accessory receptor Klotho. Both Klotho and the FGF receptor must be present for signaling. Mutations in Klotho disrupt FGF23 signaling resulting in elevated phosphate and 1,25(OH)₂D₃ levels with what has been characterized as premature aging. FGF23 production is stimulated by 1,25(OH)₂D₃ and directly or indirectly inhibited by the dentin matrix protein DMP1 found in osteocytes. Mutations in DMP1 lead to increased FGF23 levels and osteomalacia.

Interaction of PTH, Fgf23, & Vitamin D

A summary of the principal actions of PTH, FGF23, and vitamin D on the three main target tissues—intestine, kidney, and bone—is presented in Table 42–2. The net effect of PTH is to raise serum calcium and reduce serum phosphate; the net effect of FGF23 is to decrease serum phosphate; the net effect of vitamin D is to raise both. Regulation of calcium and phosphate homeostasis is achieved through a variety of feedback loops. Calcium is the principal regulator of PTH secretion. It binds to a novel ion recognition site that is part of a G_q protein–coupled receptor called the calcium sensing receptor (CaR) and links changes in intracellular free calcium concentration to changes in extracellular calcium. As serum calcium levels rise and bind to this receptor, intracellular calcium levels increase and inhibit PTH secretion. Phosphate regulates PTH secretion directly and indirectly by forming complexes with calcium in the serum. Because it is the ionized free concentration of calcium that is detected by the parathyroid gland, increases in serum phosphate levels reduce the ionized calcium and lead to enhanced PTH secretion. Such feedback regulation is appropriate to the net effect of PTH to raise serum calcium and reduce serum phosphate levels. Likewise, both calcium and phosphate at high levels reduce the amount of 1,25(OH)₂D produced by the kidney and increase the amount of 24,25(OH)₂D produced.

The high calcium works directly and indirectly by reducing PTH secretion. The high phosphate works directly and indirectly by increasing FGF23 levels. Since 1,25(OH)₂D raises serum calcium and phosphate, whereas 24,25(OH)₂D has less effect, such feedback regulation is again appropriate. 1,25(OH)₂D itself directly inhibits PTH secretion (independently of its effect on serum calcium) by a direct action on PTH gene transcription. This provides yet another negative feedback loop. The ability of 1,25(OH)₂D to inhibit PTH secretion directly is being exploited using calcitriol analogs that have less effect on serum calcium because of their lesser effect on intestinal calcium absorption. Such drugs are proving useful in the management of secondary hyperparathyroidism accompanying chronic kidney disease and may be useful in selected cases of primary hyperparathyroidism. 1,25(OH)₂D3 also stimulates the production of FGF23. This completes the negative feedback loop in that FGF23 inhibits 1,25(OH)₂D₃ production while promoting hypophosphatemia, which in turn inhibits FGF23 production and stimulates that of 1,25(OH)₂D₃.

Secondary Hormonal Regulators of Bone Mineral Homeostasis

A number of hormones modulate the actions of PTH, FGF23, and vitamin D in regulating bone mineral homeostasis. Compared with that of PTH, FGF23, and vitamin D, the physiologic impact of such secondary regulation on bone mineral homeostasis is minor. However, in pharmacologic amounts, a number of these hormones have actions on the bone mineral homeostatic mechanisms that can be exploited therapeutically.

Calcitonin

The calcitonin secreted by the parafollicular cells of the mammalian thyroid is a single-chain peptide hormone with 32 amino acids and a molecular weight of 3600. A disulfide bond between positions 1 and 7 is essential for biologic activity. Calcitonin is produced from a precursor with MW 15,000. The circulating forms of calcitonin are multiple, ranging in size from the monomer (MW 3600) to forms with an apparent MW of 60,000. Whether such heterogeneity includes precursor forms or covalently linked oligomers is not known. Because of its heterogeneity, calcitonin is standardized by bioassay in rats. Activity is compared to a standard maintained by the British Medical Research Council (MRC) and expressed as MRC units.

Human calcitonin monomer has a half-life of about 10 minutes with a metabolic clearance of 8–9 mL/kg/min. Salmon calcitonin has a longer half-life and a reduced metabolic clearance (3 mL/kg/min), making it more attractive as a therapeutic agent. Much of the clearance occurs in the kidney, although little intact calcitonin appears in the urine.

The principal effects of calcitonin are to lower serum calcium and phosphate by actions on bone and kidney. Calcitonin inhibits osteoclastic bone resorption. Although bone formation is not impaired at first after calcitonin administration, with time both formation and resorption of bone are reduced. In the kidney, calcitonin reduces both calcium and phosphate reabsorption as well as reabsorption of other ions, including sodium, potassium, and magnesium. Tissues other than bone and kidney are also affected by calcitonin. Calcitonin in pharmacologic amounts decreases gastrin secretion and reduces gastric acid output while increasing secretion of sodium, potassium, chloride, and water in the gut. Pentagastrin is a potent stimulator of calcitonin secretion (as is hypercalcemia), suggesting a possible physiologic relation between gastrin and calcitonin. In the adult human, no readily demonstrable problem develops in cases of calcitonin deficiency (thyroidectomy) or excess (medullary carcinoma of the thyroid). However, the ability of calcitonin to block bone resorption and lower serum calcium makes it a useful drug for the treatment of Paget's disease, hypercalcemia, and osteoporosis.

Glucocorticoids

Glucocorticoid hormones alter bone mineral homeostasis by antagonizing vitamin D-stimulated intestinal calcium transport, by stimulating renal calcium excretion, and by blocking bone formation. Although these observations underscore the negative impact of glucocorticoids on bone mineral homeostasis, these hormones have proved useful in reversing the hypercalcemia associated with lymphomas and granulomatous diseases such as sarcoidosis (in which production of 1,25[OH]₂D is increased) or in cases of vitamin D intoxication. Prolonged administration of glucocorticoids is a common cause of osteoporosis in adults and stunted skeletal development in children.

Estrogens

Estrogens can prevent accelerated bone loss during the immediate postmenopausal period and at least transiently increase bone in the postmenopausal woman.

The prevailing hypothesis advanced to explain these observations is that estrogens reduce the bone-resorbing action of PTH. Estrogen administration leads to an increased 1,25(OH)₂D level in blood, but estrogens have no direct effect on 1,25(OH)₂D production in vitro. The increased 1,25(OH)₂D levels in vivo following estrogen treatment may result from decreased serum calcium and phosphate and increased PTH. Estrogen receptors have been found in bone, and estrogen has direct effects on bone remodeling. Recent case reports of men who lack the estrogen receptor or who are unable to produce estrogen because of aromatase deficiency noted marked osteopenia and failure to close epiphyses. This further substantiates the role of estrogen in bone development, even in men. The principal therapeutic application for estrogen administration in disorders of bone mineral homeostasis is the treatment or prevention of postmenopausal osteoporosis. However, long-term use of estrogen is being discouraged because of its deleterious adverse effects. Rather, selective estrogen receptor modulators (SERMs) have been developed to retain the beneficial effects on bone while minimizing these deleterious adverse effects on breast, uterus, and the cardiovascular system (see Newer Therapies for Osteoporosis).

Nonhormonal Agents Affecting Bone Mineral Homeostasis

Bisphosphonates

The bisphosphonates are analogs of pyrophosphate in which the P-O-P bond has been replaced with a nonhydrolyzable P-C-P bond (Figure 42–4). Etidronate, pamidronate, and alendronate have now been joined by risedronate, tiludronate, ibandronate, and zoledronate for clinical use. The bisphosphonates owe at least part of their clinical usefulness and toxicity to their ability to retard formation and dissolution of hydroxyapatite crystals within and outside the skeletal system. They localize to regions of bone resorption and so exert their greatest effects on osteoclasts. However, the exact mechanism by which they selectively inhibit bone resorption is not clear.

The results from animal and clinical studies indicate that less than 10% of an oral dose of these drugs is absorbed. Food reduces absorption even further, necessitating their administration on an empty stomach. Because it causes gastric irritation, pamidronate is not available as an oral preparation. However, with the possible exception of etidronate, all currently available bisphosphonates have this complication. Nearly half of the absorbed drug accumulates in bone; the remainder is excreted unchanged in the urine. Decreased renal function, esophageal motility disorders, and peptic ulcer disease are the main contraindications to the use of these drugs, although the latter two complications can be circumvented using intravenous administration of pamidronate, zoledronate, and ibandronate. The portion bound to bone is retained for months, depending on the turnover of bone itself.

Etidronate and the other bisphosphonates exert a variety of effects on bone mineral homeostasis. In particular, bisphosphonates are useful for the treatment of hypercalcemia associated with malignancy, for Paget's disease, and for osteoporosis (see Newer Therapies for Osteoporosis). Contrary to expectations, some of the newer bisphosphonates appear to increase bone mineral density well beyond the 2-year period predicted for a drug whose effects are limited to blocking bone resorption. The bisphosphonates exert a variety of other cellular effects, including inhibition of 1,25(OH)₂D production, inhibition of intestinal calcium transport, metabolic changes in bone cells such as inhibition of glycolysis, inhibition of cell growth, and changes in acid and alkaline phosphatase.

Amino bisphosphonates such as alendronate and risedronate have been found to block farnesyl pyrophosphate synthase, an enzyme in the mevalonate pathway that appears to be critical for osteoclast survival. Statins, which block mevalonate synthesis, stimulate bone formation at least in animal studies. Thus, the mevalonate pathway appears to be important in bone cell function and provides new targets for drug development. These effects vary depending on the bisphosphonate being studied (ie, only amino bisphosphonates have this property) and may account for some of the clinical differences observed in the effects of the various bisphosphonates on bone mineral homeostasis. However, with the exceptions of the induction of a mineralization defect by higher than approved doses of etidronate and gastric and esophageal irritation by pamidronate and by high doses of alendronate, these drugs have proved to be remarkably free of adverse effects when used at the doses recommended for the treatment of osteoporosis. Esophageal irritation can be minimized by taking the drug with a full glass of water and remaining upright for 30 minutes. Of the other complications, osteonecrosis of the jaw (ONJ) has received considerable attention, but is rare in patients receiving the usual doses of bisphosphonates (perhaps 1/100,000 patient-years), although this complication is more frequent when high intravenous doses of zoledronate are used to control bone metastases and cancer-induced hypercalcemia.

Calcimimetics

Cinacalcet is the first representative of a new class of drugs that activates the calcium sensing receptor (CaR). CaR is widely distributed but has its greatest concentration in the parathyroid gland. Cinacalcet blocks PTH secretion by this mechanism and is approved for the treatment of secondary hyperparathyroidism in chronic kidney disease and for the treatment of parathyroid carcinoma.

Plicamycin (Mithramycin)

Plicamycin is a cytotoxic antibiotic (see Chapter 54) that has been used clinically for two disorders of bone mineral metabolism: Paget's disease and hypercalcemia. The cytotoxic properties of the drug appear to involve its binding to DNA and interruption of DNA directed RNA synthesis. The reasons for its usefulness in the treatment of Paget's disease and hypercalcemia are unclear but may relate to the need for protein synthesis to sustain bone resorption. The doses required to treat Paget's disease and hypercalcemia are about one tenth the amounts required to achieve cytotoxic effects.

Thiazides

The chemistry and pharmacology of the thiazide family of drugs are covered in Chapter 15. The principal application of thiazides in the treatment of bone mineral disorders is in reducing renal calcium excretion. Thiazides may increase the effectiveness of PTH in stimulating reabsorption of calcium by the renal tubules or may act on calcium reabsorption secondarily by increasing sodium reabsorption in the proximal tubule. In the distal tubule, thiazides block sodium reabsorption at the luminal surface, increasing the calcium-sodium exchange at the basolateral membrane and thus enhancing calcium reabsorption into the blood at this site. Thiazides have proved to be useful in reducing the hypercalciuria and incidence of stone formation in subjects with idiopathic hypercalciuria. Part of their efficacy in reducing stone formation may lie in their ability to decrease urine oxalate excretion and increase urine magnesium and zinc levels (both of which inhibit calcium oxalate stone formation).

Fluoride

Fluoride is well established as effective for the prophylaxis of dental caries and has been under investigation for the treatment of osteoporosis. Both therapeutic applications originated from epidemiologic observations that subjects living in areas with naturally fluoridated water (1–2 ppm) had less dental caries and fewer vertebral compression fractures than subjects living in nonfluoridated water areas. Fluoride is accumulated by bones and teeth, where it may stabilize the hydroxyapatite crystal. Such a mechanism may explain the effectiveness of fluoride in increasing the resistance of teeth to dental caries, but it does not explain new bone growth.

Fluoride in drinking water appears to be most effective in preventing dental caries if consumed before the eruption of the permanent teeth. The optimum concentration in drinking water supplies is 0.5–1 ppm. Topical application is most effective if done just as the teeth erupt. There is little further benefit to giving fluoride after the permanent teeth are fully formed. Excess fluoride in drinking water leads to mottling of the enamel proportionate to the concentration above 1 ppm.

Because of the paucity of agents that stimulate new bone growth in patients with osteoporosis, fluoride for this disorder has been examined (see Osteoporosis, below). Results of earlier studies indicated that fluoride alone without adequate calcium supplementation produced osteomalacia. More recent studies, in which calcium supplementation has been adequate, have demonstrated an improvement in calcium balance, an increase in bone mineral, and an increase in trabecular bone volume. However, studies of the ability of fluoride to reduce fractures reach opposite conclusions. Adverse effects observed—at the doses used for testing fluoride's effect on bone—include nausea and vomiting, gastrointestinal blood loss, arthralgias, and arthritis in a substantial proportion of patients. Such effects are usually responsive to reduction of the dose or giving fluoride with meals (or both). At present, fluoride is not approved by the Food and Drug Administration (FDA) for use in osteoporosis.

Strontium Ranelate

Strontium ranelate is composed of an organic ion, ranelic acid, bound to two atoms of strontium. Although not yet approved for use in the United States, this drug is being used in Europe for the treatment of osteoporosis. Strontium ranelate appears to block osteoclast differentiation while promoting their apoptosis and thus inhibiting bone resorption. At the same time, strontium ranelate appears to promote bone formation. Unlike bisphosphonates or teriparatide, this drug increases bone formation markers while inhibiting bone resorption markers. Large clinical trials have demonstrated its efficacy in increasing bone mineral density and decreasing fractures in the spine and hip. Toxicities reported thus far are similar to placebo.

Clinical Pharmacology

Persons with disorders of bone mineral homeostasis generally present with abnormalities in serum or urine calcium levels (or both), often accompanied by abnormal serum phosphate levels. These abnormal mineral concentrations may themselves cause symptoms requiring immediate treatment (eg, coma in malignant hypercalcemia, tetany in hypocalcemia). More commonly, they serve as clues to an underlying disorder in hormonal regulators (eg, primary hyperparathyroidism), target tissue response (eg, chronic kidney disease), or drug misuse (eg, vitamin D intoxication). In such cases, treatment of the underlying disorder is of prime importance.

Since bone and kidney play central roles in bone mineral homeostasis, conditions that alter bone mineral homeostasis usually affect one or both of these tissues secondarily. Effects on bone can result in osteoporosis (abnormal loss of bone; remaining bone histologically normal), osteomalacia (abnormal bone formation due to inadequate mineralization), or osteitis fibrosa (excessive bone resorption with fibrotic replacement of resorption cavities and marrow). Biochemical markers of skeletal involvement include changes in serum levels of the skeletal isoenzyme of alkaline phosphatase and osteocalcin (reflecting osteoblastic activity) and urine levels of hydroxyproline and pyridinoline cross-links (reflecting osteoclastic activity). The kidney becomes involved when the calcium x phosphate product in serum exceeds the point at which ectopic calcification occurs (nephrocalcinosis) or when the calcium x oxalate (or phosphate) product in urine exceeds saturation, leading to nephrolithiasis. Subtle early indicators of such renal involvement include polyuria, nocturia, and hyposthenuria. Radiologic evidence of nephrocalcinosis and stones is not generally observed until later. The degree of the ensuing renal failure is best followed by monitoring the decline in creatinine clearance. On the other hand, chronic kidney disease can be a primary cause of bone disease because of altered handling of calcium and phosphate, decreased 1,25(OH)₂D production, and secondary hyperparathyroidism.

Abnormal Serum Calcium & Phosphate Levels

Hypercalcemia

Hypercalcemia causes central nervous system depression, including coma, and is potentially lethal. Its major causes (other than thiazide therapy) are hyperparathyroidism and cancer with or without bone metastases. Less common causes are hypervitaminosis D, sarcoidosis, thyrotoxicosis, milk-alkali syndrome, adrenal insufficiency, and immobilization. With the possible exception of hypervitaminosis D, the latter disorders seldom require emergency lowering of serum calcium. A number of approaches are used to manage the hypercalcemic crisis.

Saline Diuresis

In hypercalcemia of sufficient severity to produce symptoms, rapid reduction of serum calcium is required. The first steps include rehydration with saline and diuresis with furosemide, although the efficacy of furosemide in this setting has not been proved and the drug appears to be falling out of favor. Most patients presenting with severe hypercalcemia have a substantial component of prerenal azotemia owing to dehydration, which prevents the kidney from compensating for the rise in serum calcium by excreting more calcium in the urine. Therefore, the initial infusion of 500–1000 mL/h of saline to reverse the dehydration and restore urine flow can by itself substantially lower serum calcium. The addition of a loop diuretic such as furosemide following rehydration not only enhances urine flow but also inhibits calcium reabsorption in the ascending limb of the loop of Henle (see Chapter 15). Monitoring central venous pressure is important to forestall the development of heart failure and pulmonary edema in predisposed subjects. In many subjects, saline diuresis suffices to reduce serum calcium levels to a point at which more definitive diagnosis and treatment of the underlying condition can be achieved. If this is not the case or if more prolonged medical treatment of hypercalcemia is required, the following agents are available (discussed in order of preference).

Bisphosphonates

Pamidronate, 60–90 mg, infused over 2–4 hours, and zole-dronate, 4 mg, infused over at least 15 minutes, have been approved for the treatment of hypercalcemia of malignancy and have largely replaced the less effective etidronate for this indication. The effects generally persist for weeks, but treatment can be repeated after a 7-day interval if necessary and if renal function is not impaired. Some patients experience a self-limited flu-like syndrome after the infusion. Repeated doses of these drugs have been linked to renal deterioration and osteonecrosis of the jaw, but this adverse effect is rare.

Calcitonin

Calcitonin has proved useful as ancillary treatment in a large number of patients. Calcitonin by itself seldom restores serum calcium to normal, and refractoriness frequently develops. However, its lack of toxicity permits frequent administration at high doses (200 MRC units or more). An effect on serum calcium is observed within 4–6 hours and lasts for 6–10 hours. Calcimar (salmon calcitonin) is available for parenteral and nasal administration.

Gallium Nitrate

Gallium nitrate is approved by the FDA for the management of hypercalcemia of malignancy. This drug acts by inhibiting bone resorption. At a dosage of 200 mg/m² body surface area per day given as a continuous intravenous infusion in 5% dextrose for 5 days, gallium nitrate proved superior to calcitonin in reducing serum calcium in cancer patients. Because of potential nephrotoxicity, patients should be well hydrated and have good renal output before starting the infusion.

Plicamycin (Mithramycin)

Because of its toxicity, plicamycin (mithramycin) is not the drug of first choice for the treatment of hypercalcemia. However, when other forms of therapy fail, 25–50 mcg/kg given intravenously usually lowers serum calcium substantially within 24–48 hours. This effect can last several days. This dose can be repeated as necessary. The most dangerous toxic effect is sudden thrombocytopenia followed by hemorrhage. Hepatic and renal toxicity can also occur. Hypocalcemia, nausea, and vomiting may limit therapy. Use of this drug must be accompanied by careful monitoring of platelet counts, liver and kidney function, and serum calcium levels.

Phosphate

Giving intravenous phosphate is probably the fastest and surest way to reduce serum calcium, but it is a hazardous procedure if not done properly. Intravenous phosphate should be used only after other methods of treatment (bisphosphonates, calcitonin, and saline diuresis) have failed to control symptomatic hypercalcemia. Phosphate must be given slowly (50 mmol or 1.5 g elemental phosphorus over 6–8 hours) and the patient switched to oral phosphate (1–2 g/d elemental phosphorus, as one of the salts indicated below) as soon as symptoms of hypercalcemia have cleared. The risks of intravenous phosphate therapy include sudden hypocalcemia, ectopic calcification, acute renal failure, and hypotension. Oral phosphate can also lead to ectopic calcification and renal failure if serum calcium and phosphate levels are not carefully monitored, but the risk is less and the time of onset much longer. Phosphate is available in oral and intravenous forms as sodium or potassium salt. Amounts required to provide 1 g of elemental phosphorus are as follows:

Intravenous:

In-Phos: 40 mL

Hyper-Phos-K: 15 mL

Oral:

Fleet Phospho-Soda: 6.2 mL

Neutra-Phos: 300 mL

K-Phos-Neutral: 4 tablets

Glucocorticoids

Glucocorticoids have no clear role in the immediate treatment of hypercalcemia. However, the chronic hypercalcemia of sarcoidosis, vitamin D intoxication, and certain cancers may respond within several days to glucocorticoid therapy. Prednisone in oral doses of 30–60 mg daily is generally used, although equivalent doses of other glucocorticoids are effective. The rationale for the use of glucocorticoids in these diseases differs, however. The hypercalcemia of sarcoidosis is secondary to increased production of 1,25(OH)₂D, possibly by the sarcoid tissue itself. Glucocorticoid therapy directed at the reduction of sarcoid tissue results in restoration of normal serum calcium and 1,25(OH)₂D levels. The treatment of hypervitaminosis D with glucocorticoids probably does not alter vitamin D metabolism significantly but is thought to reduce vitamin D-mediated intestinal calcium transport. An action of glucocorticoids to reduce vitamin D-mediated bone resorption has not been excluded, however. The effect of glucocorticoids on the hypercalcemia of cancer is probably twofold. The malignancies responding best to glucocorticoids (ie, multiple myeloma and related lymphoproliferative diseases) are sensitive to the lytic action of glucocorticoids. Therefore part of the effect may be related to decreased tumor mass and activity. Glucocorticoids have also been shown to inhibit the secretion or effectiveness of cytokines elaborated by multiple myeloma and related cancers that stimulate osteoclastic bone resorption. Other causes of hypercalcemia—particularly primary hyperparathyroidism—do not respond to glucocorticoid therapy.

Hypocalcemia

The main features of hypocalcemia are neuromuscular—tetany, paresthesias, laryngospasm, muscle cramps, and convulsions. The major causes of hypocalcemia in the adult are hypoparathyroidism, vitamin D deficiency, chronic kidney disease, and malabsorption. Neonatal hypocalcemia is a common disorder that usually resolves without therapy. The roles of PTH, vitamin D, and calcitonin in the neonatal syndrome are under active investigation. Large infusions of citrated blood can produce hypocalcemia by the formation of citrate-calcium complexes. Calcium and vitamin D (or its metabolites) form the mainstay of treatment of hypocalcemia.

Calcium

A number of calcium preparations are available for intravenous, intramuscular, and oral use. Calcium gluceptate (0.9 mEq calcium/mL), calcium gluconate (0.45 mEq calcium/mL), and calcium chloride (0.68–1.36 mEq calcium/mL) are available for intravenous therapy. Calcium gluconate is the preferred form because it is less irritating to veins. Oral preparations include calcium carbonate (40% calcium), calcium lactate (13% calcium), calcium phosphate (25% calcium), and calcium citrate (21% calcium). Calcium carbonate is often the preparation of choice because of its high percentage of calcium, ready availability (eg, Tums), low cost, and antacid properties. In achlorhydric patients, calcium carbonate should be given with meals to increase absorption, or the patient should be switched to calcium citrate, which is somewhat better absorbed. Combinations of vitamin D and calcium are available, but treatment must be tailored to the individual patient and the individual disease, a flexibility lost by fixed-dosage combinations.

Treatment of severe symptomatic hypocalcemia can be accomplished with slow infusion of 5–20 mL of 10% calcium gluconate. Rapid infusion can lead to cardiac arrhythmias. Less severe hypocalcemia is best treated with oral forms sufficient to provide approximately 400–1200 mg of elemental calcium (1–3 g calcium carbonate) per day. Dosage must be adjusted to avoid hypercalcemia and hypercalciuria.

Vitamin D

When rapidity of action is required, 1,25(OH)₂D₃ (calcitriol), 0.25–1 mcg daily, is the vitamin D metabolite of choice, because it is capable of raising serum calcium within 24–48 hours. Calcitriol also raises serum phosphate, although this action is usually not observed early in treatment. The combined effects of calcitriol and all other vitamin D metabolites and analogs on both calcium and phosphate make careful monitoring of these mineral levels especially important to prevent ectopic calcification secondary to an abnormally high serum calcium x phosphate product. Since the choice of the appropriate vitamin D metabolite or analog for long-term treatment of hypocalcemia depends on the nature of the underlying disease, further discussion of vitamin D treatment is found under the headings of the specific diseases.

Hyperphosphatemia

Hyperphosphatemia is a common complication of renal failure but is also found in all types of hypoparathyroidism (idiopathic, surgical, and pseudohypoparathyroidism), vitamin D intoxication, and the rare syndrome of tumoral calcinosis. Emergency treatment of hyperphosphatemia is seldom necessary but can be achieved by dialysis or glucose and insulin infusions. In general, control of hyperphosphatemia involves restriction of dietary phosphate plus the use of phosphate-binding gels such as sevelamer and of calcium supplements. Because of their potential to induce aluminum-associated bone disease, aluminum-containing antacids should be used sparingly and only when other measures fail to control the hyperphosphatemia.

Hypophosphatemia

A variety of conditions are associated with hypophosphatemia, including primary hyperparathyroidism, vitamin D deficiency, idiopathic hypercalciuria, X-linked and autosomal dominant hypophosphatemic rickets, tumor-induced osteomalacia, various other forms of renal phosphate wasting (eg, Fanconi's syndrome), overzealous use of phosphate binders, and parenteral nutrition with inadequate phosphate content. Acute hypophosphatemia may lead to a reduction in the intracellular levels of high-energy organic phosphates (eg, ATP), interfere with normal hemoglobin-to-tissue oxygen transfer by decreasing red cell 2,3-diphosphoglycerate levels, and lead to rhabdomyolysis. However, clinically significant acute effects of hypophosphatemia are seldom seen, and emergency treatment is generally not indicated. The long-term effects of hypophosphatemia include proximal muscle weakness and abnormal bone mineralization (osteomalacia). Therefore, hypophosphatemia should be avoided during other forms of therapy and treated in conditions such as the various forms of hypophosphatemic rickets, of which hypophosphatemia is a cardinal feature. Oral forms of phosphate available for use are listed above in latter section on hypercalcemia.

Specific Disorders Involving the Bone Mineral-Regulating Hormones

Primary Hyperparathyroidism

This rather common disease, if associated with symptoms and significant hypercalcemia, is best treated surgically. Oral phosphate and bisphosphonates have been tried but cannot be recommended. Asymptomatic patients with mild disease often do not get worse and may be left untreated. The calcimimetic agent cinacalcet, discussed previously, has been approved for secondary hyperparathyroidism and is in clinical trials for the treatment of primary hyperparathyroidism. If such drugs prove efficacious, medical management of this disease will need to be reconsidered.

Hypoparathyroidism

In the absence of PTH (idiopathic or surgical hypoparathyroidism) or an abnormal target tissue response to PTH (pseudohypoparathyroidism), serum calcium falls and serum phosphate rises. In such patients, 1,25(OH)₂D levels are usually low, presumably reflecting the lack of stimulation by PTH of 1,25(OH)₂D production. The skeletons of patients with idiopathic or surgical hypoparathyroidism are normal except for a slow turnover rate. A number of patients with pseudohypoparathyroidism appear to have osteitis fibrosa, suggesting that the normal or high PTH levels found in such patients are capable of acting on bone but not on the kidney. The distinction between pseudohypoparathyroidism and idiopathic hypoparathyroidism is made on the basis of normal or high PTH levels but deficient renal response (ie, diminished excretion of cAMP or phosphate) in patients with pseudohypoparathyroidism.

The principal therapeutic concern is to restore normocalcemia and normophosphatemia. Under most circumstances, vitamin D (25,000–100,000 units three times per week) and dietary calcium supplements suffice. More rapid increments in serum calcium can be achieved with calcitriol, although it is not clear whether this metabolite offers a substantial advantage over vitamin D itself for long-term therapy. Many patients treated with vitamin D develop episodes of hypercalcemia. This complication is more rapidly reversible with cessation of therapy using calcitriol rather than vitamin D. This would be of importance to the patient in whom such hypercalcemic crises are common. Although teriparatide (PTH 1-34) is not approved for the treatment of hypoparathyroidism, it can be effective in patients who respond poorly to calcium and vitamin D.

Nutritional Vitamin D Deficiency or Insufficiency

The level of vitamin D thought to be necessary for good health is undergoing reexamination with the appreciation that vitamin D acts on a large number of cell types, not just those responsible for bone and mineral metabolism. Maintaining a level of 25(OH)D above 10 ng/mL is necessary for preventing rickets or osteomalacia. However, substantial epidemiologic and some prospective trial data indicate that a higher level, such as 30 ng/mL, is required to optimize intestinal calcium absorption, optimize the accrual and maintenance of bone mass, reduce falls and fractures, and prevent a wide variety of diseases including diabetes mellitus, hyperparathyroidism, autoimmune diseases, and cancer. Current recommendations are for a daily intake of 800–1200 units of vitamin D. Vitamin D deficiency or insufficiency can be treated by higher dosages (4000 units per day or 50,000 units per week for several weeks). No other metabolite is indicated. The diet should also contain adequate amounts of calcium and phosphate.

Chronic Kidney Disease

The major problems of chronic kidney disease that impact bone mineral homeostasis are the loss of 1,25(OH)₂D production, the retention of phosphate that reduces ionized calcium levels, and the secondary hyperparathyroidism that results. With the loss of 1,25(OH)₂D production, less calcium is absorbed from the intestine and less bone is resorbed under the influence of PTH. As a result hypocalcemia usually develops, furthering the development of hyperparathyroidism. The bones show a mixture of osteomalacia and osteitis fibrosa.

In contrast to the hypocalcemia that is more often associated with chronic kidney disease, some patients may become hypercalcemic from two other possible causes (in addition to overzealous treatment with calcium). The most common cause of hypercalcemia is the development of severe secondary (sometimes referred to as tertiary) hyperparathyroidism. In such cases, the PTH level in blood is very high. Serum alkaline phosphatase levels also tend to be high. Treatment often requires parathyroidectomy.

A less common circumstance leading to hypercalcemia is development of a form of bone disease characterized by a profound decrease in bone cell activity and loss of the calcium buffering action of bone (adynamic bone disease). In the absence of kidney function, any calcium absorbed from the intestine accumulates in the blood. Therefore, such patients are very sensitive to the hypercalcemic action of 1,25(OH)₂D. These individuals generally have a high serum calcium but nearly normal alkaline phosphatase and PTH levels. The bone in such patients may have a high aluminum content, especially in the mineralization front, which blocks normal bone mineralization. These patients do not respond favorably to parathyroidectomy. Deferoxamine, an agent used to chelate iron (see Chapter 57), also binds aluminum and is being used as therapy for this disorder. However, with less use of aluminum-containing phosphate binders, most cases of adynamic bone disease are not associated with aluminum deposition but are attributed to overzealous suppression of PTH secretion.

Vitamin D Preparations

The choice of vitamin D preparation to be used in the setting of chronic kidney disease depends on the type and extent of bone disease and hyperparathyroidism. Individuals with vitamin D deficiency or insufficiency should first have their 25(OH)D levels restored to normal (above 30 ng/mL) with vitamin D. 1,25(OH)₂D3 (calcitriol) rapidly corrects hypocalcemia and at least partially reverses the secondary hyperparathyroidism and osteitis fibrosa. Many patients with muscle weakness and bone pain gain an improved sense of well-being.

Two analogs of calcitriol—doxercalciferol and paricalcitol—are approved for the treatment of secondary hyperparathyroidism of chronic kidney disease. Their principal advantage is that they are less likely than calcitriol to induce hypercalcemia for any given reduction in PTH. Their greatest impact is in patients in whom the use of calcitriol may lead to unacceptably high serum calcium levels.

Regardless of the drug used, careful attention to serum calcium and phosphate levels is required. A calcium ¥ phosphate product (in mg/dL units) less than 55 is desired with both calcium and phosphate in the normal range. Calcium adjustments in the diet and dialysis bath and phosphate restriction (dietary and with oral ingestion of phosphate binders) should be used along with vitamin D metabolites. Monitoring serum PTH and alkaline phosphatase levels is useful in determining whether therapy is correcting or preventing secondary hyperparathyroidism. Although not generally available, percutaneous bone biopsies for quantitative histomorphometry may help in choosing appropriate therapy and following the effectiveness of such therapy, especially in cases suspected of having adynamic bone disease. Unlike the rapid changes in serum values, changes in bone morphology require months to years. Monitoring serum levels of the vitamin D metabolites is useful for determining compliance, absorption, and metabolism.

Intestinal Osteodystrophy

A number of gastrointestinal and hepatic diseases result in disordered calcium and phosphate homeostasis, which ultimately leads to bone disease. The bones in such patients show a combination of osteoporosis and osteomalacia. Osteitis fibrosa does not occur, as in renal osteodystrophy. The common features that appear to be important in this group of diseases are malabsorption of calcium and malabsorption of vitamin D. Liver disease may, in addition, reduce the production of 25(OH)D from vitamin D, although its importance in all but patients with terminal liver failure remains in dispute. The malabsorption of vitamin D is probably not limited to exogenous vitamin D. The liver secretes into bile a substantial number of vitamin D metabolites and conjugates that are reabsorbed in (presumably) the distal jejunum and ileum. Interference with this process could deplete the body of endogenous vitamin D metabolites as well as limit absorption of dietary vitamin D.

In mild forms of malabsorption, vitamin D (25,000–50,000 units three times per week) should suffice to raise serum levels of 25(OH)D into the normal range. Many patients with severe disease do not respond to vitamin D. Clinical experience with the other metabolites is limited, but both calcitriol and calcifediol have been used successfully in doses similar to those recommended for treatment of renal osteodystrophy. Theoretically, calcifediol should be the drug of choice under these conditions, because no impairment of the renal metabolism of 25(OH)D to 1,25(OH)₂D and 24,25(OH)₂D exists in these patients. Both calcitriol and 24,25(OH)₂D may be of importance in reversing the bone disease. However, calcifediol is no longer available.

As in the other diseases discussed, treatment of intestinal osteodystrophy with vitamin D and its metabolites should be accompanied by appropriate dietary calcium supplementation and monitoring of serum calcium and phosphate levels.

Osteoporosis

Osteoporosis is defined as abnormal loss of bone predisposing to fractures. It is most common in postmenopausal women but also occurs in men. The annual cost of fractures in older women and men in the USA was estimated at $13.8 billion in 1996 and would be much higher today. It may occur as an adverse effect of long-term administration of glucocorticoids or other drugs; as a manifestation of endocrine disease such as thyrotoxicosis or hyperparathyroidism; as a feature of malabsorption syndrome; as a consequence of alcohol abuse and cigarette smoking; or without obvious cause (idiopathic). The ability of some agents to reverse the bone loss of osteoporosis is shown in Figure 42–5. The postmenopausal form of osteoporosis may be accompanied by lower 1,25(OH)₂D levels and reduced intestinal calcium transport. This form of osteoporosis is due to estrogen deficiency and can be treated with estrogen (cycled with a progestin in women with a uterus to prevent endometrial carcinoma). However, concern that estrogen increases the risk of breast cancer and fails to reduce the development of heart disease has reduced enthusiasm for this form of therapy.

As previously noted, estrogen-like SERMs (selective estrogen receptor modulators, Chapter 40) have been developed that prevent the increased risk of breast and uterine cancer associated with estrogen while maintaining the benefit to bone. Raloxifene is such a drug approved for treatment of osteoporosis. Like tamoxifen, it appears to reduce the risk of breast cancer. Raloxifene protects against spine fractures but not hip fractures—unlike bisphosphonates and teriparatide, which protect against both. Raloxifene does not prevent hot flushes and imposes the same increased risk of thrombophlebitis as estrogen. To counter the reduced intestinal calcium transport associated with osteoporosis, vitamin D therapy is often used in addition to dietary calcium supplementation. There is no clear evidence that pharmacologic doses of vitamin D are of much additional benefit beyond cyclic estrogens and calcium supplementation. However, in several large studies, vitamin D supplementation (800 IU/d) has been shown to be useful. In addition, calcitriol and its analog 1(OH)D3 have been shown to increase bone mass and reduce fractures in several recent studies. Use of these agents for osteoporosis is not FDA-approved, although they are used in other countries.

Despite early promise that fluoride might be useful in the prevention or treatment of postmenopausal osteoporosis, this form of therapy remains controversial. A new formulation of fluoride (slow release, lower dose) appears to avoid much of the toxicity of earlier formulations and may reduce fracture rates. However, this formulation has not been approved by the FDA.

Teriparatide, the recombinant form of PTH 1-34, is approved for treatment of osteoporosis. Teriparatide is given in a dosage of 20 mcg subcutaneously daily. Like fluoride, teriparatide stimulates new bone formation, but unlike fluoride, this new bone appears structurally normal and is associated with a substantial reduction in the incidence of fractures. Teriparatide is approved for use for only 2 years. Trials examining the sequential use of teriparatide followed by a bisphosphonate after 1 or 2 years are in progress and look promising. Giving teriparatide with a bisphosphonate has not shown greater efficacy than the bisphosphonate alone.

Calcitonin is approved for use in the treatment of postmenopausal osteoporosis. It has been shown to increase bone mass and reduce fractures, but only in the spine. It does not appear to be as effective as bisphosphonates or teriparatide.

Bisphosphonates are potent inhibitors of bone resorption. They increase bone density and reduce the risk of fractures in the hip, spine, and other locations. Alendronate, risedronate, ibandronate, and zoledronate are approved for the treatment of osteoporosis, using daily dosing schedules of alendronate 10 mg/d, risedronate 5 mg/d, ibandronate 2.5 mg/d; or weekly schedules of alendronate 70 mg/wk, risedronate 35 mg/wk; or monthly schedules of ibandronate 150 mg/mo; or quarterly (every 3 months) injections of 3 mg ibandronate; or annual infusions of zoledronate 5 mg. These drugs are effective in men as well as women and for various causes of osteoporosis.

Strontium ranelate has not been approved in the United States for the treatment of osteoporosis but is being used in Europe, generally at a dose of 2 g/d. Denosumab, an antibody to RANKL that suppresses bone resorption by interfering with RANKL/RANK induction of osteoclast differentiation and function, has shown good efficacy in phase 3 trials and may be approved for clinical use in the near future.

X-Linked & Autosomal Dominant Hypophosphatemia

These disorders are manifested by the appearance of rickets and hypophosphatemia in children, although they may first present in adults. X-linked hypophosphatemia is caused by mutations in a gene encoding the PHEX protein, which appears to be an endopeptidase. Mutations in the gene responsible for the autosomal dominant form target FGF23 (fibroblast growth factor 23). The current concept is that FGF23 blocks the renal uptake of phosphate and blocks 1,25(OH)₂D3 production. Mutations in PHEX inactivate it, and FGF23 levels increase. Similarly, mutations in FGF23 that resist hydrolysis, as seen in patients with the autosomal form of hypophosphatemic rickets, also result in elevated FGF23 levels.

Initially, it was thought that FGF23 was a direct substrate for PHEX, but this no longer appears to be the case. In either disease, intact and biologically active FGF23 accumulates, leading to phosphate wasting in the urine and hypophosphatemia.

Phosphate is critical to normal bone mineralization; when phosphate stores are deficient, a clinical and pathologic picture resembling vitamin D–deficient rickets develops. However, affected children fail to respond to the usual doses of vitamin D used in the treatment of nutritional rickets. A defect in 1,25(OH)₂D production by the kidney has also been noted, because the serum 1,25(OH)₂D levels tend to be low in comparison with the degree of hypophosphatemia observed. This combination of low serum phosphate and low or low-normal serum 1,25(OH)₂D provides the rationale for treating such patients with oral phosphate (1–3 g daily) and calcitriol (0.25–2 mcg daily). Reports of such combination therapy are encouraging in this otherwise debilitating disease.

Vitamin D–Dependent Rickets Types I & II

These distinctly different autosomal recessive diseases present as childhood rickets that do not respond to conventional doses of vitamin D. Type I vitamin D–dependent rickets, now known as pseudovitamin D deficiency rickets, is due to an isolated deficiency of 1,25(OH)₂D production caused by mutations in 25(OH)D-1-hydroxylase (CYP27B1). This condition can be treated with vitamin D (4000 units daily) or calcitriol (0.25–0.5 mcg daily). Type II vitamin D–dependent rickets, now known as hereditary vitamin D resistant rickets, is caused by mutations in the gene for the vitamin D receptor, which disrupt the functions of this receptor and lead to this syndrome. The serum lev-els of 1,25(OH)₂D are very high in type II but not in type I vitamin D–dependent rickets. Treatment with large doses of calcitriol has been claimed to be effective in restoring normocalcemia in some patients, presumably those with a partially functional vitamin D receptor, although many patients are completely resistant to all forms of vitamin D. Calcium and phosphate infusions have been shown to correct the osteomalacia in some children, similar to studies in mice in which the VDR gene has been deleted. These diseases are rare.

Nephrotic Syndrome

Patients with nephrotic syndrome can lose vitamin D metabolites in the urine, presumably by loss of the vitamin D-binding protein. Such patients may have very low 25(OH)D levels. Some of them develop bone disease. It is not yet clear what value vitamin D therapy has in such patients, because therapeutic trials with vitamin D (or any other vitamin D metabolite) have not yet been carried out. Because the problem is not related to vitamin D metabolism, one would not anticipate any advantage in using the more expensive vitamin D metabolites in place of vitamin D itself.

Idiopathic Hypercalciuria

People with idiopathic hypercalciuria, characterized by hypercalciuria and nephrolithiasis with normal serum calcium and PTH levels, have been divided into three groups: (1) hyperabsorbers, patients with increased intestinal absorption of calcium, resulting in high-normal serum calcium, low-normal PTH, and a secondary increase in urine calcium; (2) renal calcium leakers, patients with a primary decrease in renal reabsorption of filtered calcium, leading to low-normal serum calcium and high-normal serum PTH; and (3) renal phosphate leakers, patients with a primary decrease in renal reabsorption of phosphate, leading to stimulation of 1,25(OH)₂D production, increased intestinal calcium absorption, increased ionized serum calcium, low-normal PTH levels, and a secondary increase in urine calcium. There is some disagreement about this classification, and many patients are not readily categorized. Many such patients present with mild hypophosphatemia, and oral phosphate has been used with some success in reducing stone formation. However, a clear role for phosphate in the treatment of this disorder has not been established.

Therapy with hydrochlorothiazide, up to 50 mg twice daily, or chlorthalidone, 50–100 mg daily, is recommended. Loop diuretics such as furosemide and ethacrynic acid should not be used because they increase urinary calcium excretion. The major toxicity of thiazide diuretics, besides hypokalemia, hypomagnesemia, and hyperglycemia, is hypercalcemia. This is seldom more than a biochemical observation unless the patient has a disease such as hyperparathyroidism in which bone turnover is accelerated. Accordingly, one should screen patients for such disorders before starting thiazide therapy and monitor serum and urine calcium when therapy has begun.

An alternative to thiazides is allopurinol. Some studies indicate that hyperuricosuria is associated with idiopathic hypercalcemia and that a small nidus of urate crystals could lead to the calcium oxalate stone formation characteristic of idiopathic hypercalcemia. Allopurinol, 300 mg daily, may reduce stone formation by reducing uric acid excretion.

Other Disorders of Bone Mineral Homeostasis

Paget's Disease of Bone

Paget's disease is a localized bone disease characterized by uncontrolled osteoclastic bone resorption with secondary increases in bone formation. This new bone is poorly organized, however. The cause of Paget's disease is obscure, although some studies suggest that a slow virus may be involved. The disease is fairly common, although symptomatic bone disease is less common. The biochemical parameters of elevated serum alkaline phosphatase and urinary hydroxyproline are useful for diagnosis. Along with the characteristic radiologic and bone scan findings, these biochemical determinations provide good markers by which to follow therapy.

The goal of treatment is to reduce bone pain and stabilize or prevent other problems such as progressive deformity, hearing loss, high-output cardiac failure, and immobilization hypercalcemia. Calcitonin and bisphosphonates are the first-line agents for this disease. Treatment failures may respond to plicamycin. Calcitonin is administered subcutaneously or intramuscularly in doses of 50–100 MRC (Medical Research Council) units every day or every other day. Nasal inhalation at 200–400 units per day is also effective. Higher or more frequent doses have been advocated when this initial regimen is ineffective. Improvement in bone pain and reduction in serum alkaline phosphatase and urine hydroxyproline levels require weeks to months. Often a patient who responds well initially loses the response to calcitonin. This refractoriness is not correlated with the development of antibodies.

Sodium etidronate, alendronate, risedronate, and tiludro-nate are the bisphosphonates currently approved for clinical use in Paget's disease of bone in the USA. However, other bisphosphonates, including pamidronate, are being used in other countries. The recommended dosages of bisphosphonates are etidronate, 5 mg/kg/d; alendronate, 40 mg/d; risedronate, 30 mg/d; and tiludronate, 400 mg/d. Long-term (months to years) remission may be expected in patients who respond to these agents. Treatment should not exceed 6 months per course but can be repeated after 6 months if necessary. The principal toxicity of etidronate is the development of osteomalacia and an increased incidence of fractures when the dosage is raised substantially above 5 mg/kg/d. The newer bisphosphonates such as risedronate and alendronate do not share this adverse effect. Some patients treated with etidro-nate develop bone pain similar in nature to the bone pain of osteomalacia. This subsides after stopping the drug. The principal adverse effect of alendronate and the newer bisphosphonates is gastric irritation when used at these high doses. This is reversible on cessation of the drug.

The use of a potentially lethal cytotoxic drug such as plicamycin in a generally benign disorder such as Paget's disease is recommended only when other less toxic agents (calcitonin, alendronate) have failed and the symptoms are debilitating. Clinical data on long-term use of plicamycin are insufficient to determine its usefulness for extended therapy. However, short courses involving 15–25 mcg/kg/d intravenously for 5–10 days followed by 15 mcg/kg intravenously each week have been used to control the disease.

Enteric Oxaluria

Patients with short bowel syndromes associated with fat malabsorption can present with renal stones composed of calcium and oxalate. Such patients characteristically have normal or low urine calcium levels but elevated urine oxalate levels. The reasons for the development of oxaluria in such patients are thought to be two-fold: first, in the intestinal lumen, calcium (which is now bound to fat) fails to bind oxalate and no longer prevents its absorption; second, enteric flora, acting on the increased supply of nutrients reaching the colon, produce larger amounts of oxalate. Although one would ordinarily avoid treating a patient with calcium oxalate stones with calcium supplementation, this is precisely what is done in patients with enteric oxaluria. The increased intestinal calcium binds the excess oxalate and prevents its absorption. One to 2 g of calcium carbonate can be given daily in divided doses, with careful monitoring of urinary calcium and oxalate to be certain that urinary oxalate falls without a dangerous increase in urinary calcium.

Summary: Major Drugs Used in Diseases of Bone Mineral Homeostasis

Preparations Available

Vitamin D, Metabolites, and Analogs

Calcium

Phosphate and Phosphate Binder

Other Drugs

References