Basic and Clinical Pharmacology, 13th Ed.

Agents That Affect Bone Mineral Homeostasis

Daniel D. Bikle, MD, PhD


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 degenerative changes. The hip measurement shows a T score (number of standard deviations by which the patient’s measured bone density differs from that of a normal young adult) in the femoral neck of –2.2. What further workup should be considered, and what therapy should be initiated?


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 complex mechanisms to carefully maintain calcium and phosphate homeostasis (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. This reservoir is 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. This relationship is more than fortuitous as elements of the bone marrow affect skeletal processes just as skeletal elements affect hematopoeitic processes. During aging and in nutritional diseases such as anorexia nervosa and obesity, fat accumulates in the marrow, suggesting a dynamic interaction between marrow fat and bone. Abnormalities in bone mineral homeostasis can lead to a wide variety of cellular dysfunctions (eg, tetany, coma, muscle weakness), and to disturbances in structural support of the body (eg, osteoporosis with fractures) and loss of hematopoietic capacity (eg, infantile osteopetrosis).


FIGURE 42–1 Mechanisms contributing to bone mineral homeostasis. Serum calcium (Ca) and phosphorus (P) concentrations are controlled principally by three hormones, 1,25-dihydroxyvitamin D (D), fibroblast growth factor 23 (FGF23), and parathyroid hormone (PTH), through their action on absorption from the gut and from bone and on renal excretion. PTH and 1,25(OH)2D increase the input of calcium and phosphorus from bone into the serum and stimulate bone formation. 1,25(OH)2D also increases calcium and phosphate absorption from the gut. In the kidney, 1,25(OH)2D decreases excretion of both calcium and phosphorus, whereas PTH reduces calcium but increases phosphorus excretion. FGF23 stimulates renal excretion of phosphate. Calcitonin (CT) is a less critical regulator of calcium homeostasis, but in pharmacologic concentrations can reduce serum calcium and phosphorus by inhibiting bone resorption and stimulating their renal excretion. Feedback may alter the effects shown; for example, 1,25(OH)2D increases urinary calcium excretion indirectly through increased calcium absorption from the gut and inhibition of PTH secretion and may increase urinary phosphate excretion because of increased phosphate absorption from the gut and stimulation of FGF23 production.

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 amount represents net absorption, because both absorption (principally in the duodenum and upper jejunum) and secretion (principally in the ileum) occur. The quantity 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. Dysfunction of the intestine (eg, nontropical sprue) or kidney (eg, chronic renal failure) can disrupt bone mineral homeostasis.

Three hormones serve as the principal regulators of calcium and phosphate homeostasis: parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), and vitamin D via its active metabolite 1,25-dihydroxyvitamin D (1,25(OH)2D (Figure 42–2). The role of calcitonin (CT) is less critical during adult life but may play a greater role during pregnancy and lactation. The term vitamin D, when used without a subscript, refers to both vitamin D2(ergocalciferol) and vitamin D3 (cholecalciferol). This applies also to the metabolites of vitamin D2 and D3. Vitamin D2 and its metabolites differ from vitamin D3 and its metabolites only in the side chain where they contain a double bond between C-22–23 and a methyl group at C-24 (Figure 42–3). Vitamin D is considered a prohormone because it must be further metabolized to gain biologic activity (Figure 42–3). Vitamin D3 is produced in the skin under ultraviolet B (UVB) radiation (eg, in sunlight) from its precursor, 7-dehydrocholesterol. The initial product, pre-vitamin D3, undergoes a temperature-sensitive isomerization to vitamin D3. The precursor of vitamin D2 is ergosterol, found in plants and fungi (mushrooms). It undergoes a similar transformation to vitamin D2 with UVB radiation. Vitamin D2 thus comes only from the diet, whereas vitamin D3 comes from the skin or the diet, or both. The subsequent metabolism of these two forms of vitamin D is essentially the same and follows the illustration for vitamin D3 metabolism in Figure 42–3. The first step is the 25-hydroxylation of vitamin D to 25-hydroxyvitamin D (25[OH]D). A number of enzymes in the liver and other tissues perform this function, of which CYP2R1 is the most important. 25(OH)D is then metabolized to the active hormone 1,25-dihydroxyvitamin D (1,25[OH]2D) in the kidney and elsewhere. PTH stimulates the production of 1,25(OH)2D in the kidney, whereas FGF23 is inhibitory. Elevated levels of blood phosphate and calcium also inhibit 1,25(OH)2D production in part by their effects on FGF23 (high phosphate stimulates FGF23 production) and PTH (high calcium inhibits PTH production). 1,25(OH)2D inhibits its own production but, at least as important, it stimulates the enzyme 24-hydroxyase (CYP24A1), which begins the catabolism of 1,25(OH)2D, suppresses PTH production, and stimulates FGF23 production, all of which conspire to reduce 1,25(OH)2D levels. Other tissues also produce 1,25(OH)2D; the control of this production differs from that in the kidney, as will be discussed subsequently. The complex interplay among PTH, FGF23, and 1,25(OH)2D is discussed in detail later.


FIGURE 42–2 The hormonal interactions controlling bone mineral homeostasis. In the body (A), 1,25-dihydroxyvitamin D (1,25[OH]2D) is produced by the kidney under the control of parathyroid hormone (PTH), which stimulates its production, and fibroblast growth factor 23 (FGF23), which inhibits its production. 1,25(OH)2D in turn inhibits the production of PTH by the parathyroid glands and stimulates FGF23 release from bone. 1,25(OH)2D is the principal regulator of intestinal calcium and phosphate absorption. At the level of the bone (B), both PTH and 1,25(OH)2D regulate bone formation and resorption, with each capable of stimulating both processes. This is accomplished by their stimulation of preosteoblast proliferation and differentiation into osteoblasts, the bone-forming cell. PTH also stimulates osteoblast formation indirectly by inhibiting the osteocyte’s production of sclerostin, a protein that blocks osteoblast proliferation by inhibiting the wnt pathway (not shown). PTH and 1,25(OH)2D stimulate the expression of RANKL by the osteoblast, which, with MCSF, stimulates the differentiation and subsequent activation of osteoclasts, the bone-resorbing cell. OPG blocks RANKL action, and may be inhibited by PTH and 1,25(OH)2D. FGF23 in excess leads to osteomalacia indirectly by inhibiting 1,25(OH)2D production and lowering phosphate levels. MCSF, macrophage colony-stimulating factor; OPG, osteoprotegerin; RANKL, ligand for receptor for activation of nuclear factor-κB.


FIGURE 42–3 Conversion of 7-dehydrocholesterol to vitamin D3 in the skin and its subsequent metabolism to 25-hydroxyvitamin D3 (25[OH]D3) in the liver and to 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) and 24,25-dihydroxyvitamin D3 (24,25[OH]2D3) in the kidney. Control of vitamin D metabolism is exerted primarily at the level of the kidney, where high concentrations of serum phosphorus (P) and calcium (Ca) as well as fibroblast growth factor 23 (FGF23) inhibit production of 1,25(OH)2D3 (indicated by a minus [−] sign), but promote that of 24,25(OH)2D3 (indicated by a plus [+] sign). Parathyroid hormone (PTH), on the other hand, stimulates 1,25(OH)2D3production but inhibits 24,25(OH)2D3 production. The insert (shaded) shows the side chain for ergosterol, vitamin D2, and the active vitamin D2 metabolites. Ergosterol is converted to vitamin D2 (ergocalciferol) by UV radiation similar to the conversion of 7-dehydrocholesterol to vitamin D3. Vitamin D2, in turn, is metabolized to 25-hydroxyvitamin D2, 1,25-dihydroxyvitamin D2, and 24,25-dihydroxyvitamin D2 via the same enzymes that metabolize vitamin D3. In humans, corresponding D2 and D3 metabolites have equivalent biologic effects, although they differ in pharmacokinetics. +, facilitation; –, inhibition; P, phosphorus; Ca, calcium; PTH, parathyroid hormone; FGF23, fibroblast growth factor 23.

To summarize: 1,25(OH)2D suppresses the production of PTH as does calcium, but stimulates the production of FGF23. Phosphate stimulates both PTH and FGF23 secretion. In turn PTH stimulates 1,25(OH)2D production, whereas FGF23 is inhibitory. 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 as does FGF23, whereas 1,25(OH)2D promotes renal reabsorption of phosphate.

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 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.



Parathyroid hormone (PTH) is a single-chain peptide hormone composed of 84 amino acids. It is produced in the parathyroid 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, thereby providing one mechanism by which calcium limits the production of PTH. A second mechanism involves the calcium-sensing receptor (CaSR) which, when stimulated by calcium, reduces PTH production and secretion. The parathyroid gland also contains the vitamin D receptor (VDR) and the enzyme, CYP27B1, that produces 1,25(OH)2D, thus enabling circulating or endogenously produced 1,25(OH)2D to suppress PTH production. 1,25(OH)2D also induces the CaSR, making the parathyroid gland more sensitive to suppression by calcium. Biologic activity resides in the amino terminal region of PTH such that synthetic PTH 1-34 (available as teriparatide) 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 inactive carboxyl terminal fragments produced by metabolism of the intact hormone have a much lower clearance, especially in renal failure. In the past, this accounted for the very high PTH values observed in patients with renal failure when the hormone was measured by radioimmunoassays directed against the carboxyl terminal region. Currently, most PTH assays differentiate between intact PTH 1-34 and large inactive fragments, so that it is possible to more accurately evaluate biologically active PTH status in patients with renal failure.

PTH regulates calcium and phosphate flux across cellular membranes in bone and kidney, resulting in increased serum calcium and decreased serum phosphate (Figure 42–1). In bone, PTH increases the activity and number of osteoclasts, the cells responsible for bone resorption (Figure 42–2). However, this stimulation of osteoclasts is not a direct effect. Rather, PTH acts on the osteoblast (the bone-forming cell) to induce membrane-bound and secreted soluble forms of a protein called RANK ligand (RANKL). RANKL acts on osteoclasts and osteoclast precursors to increase both the numbers and activity of osteoclasts. This action increases bone remodeling, a specific sequence of cellular events initiated by osteoclastic bone resorption and followed by osteoblastic bone formation. Denosumab, an antibody that inhibits the action of RANKL, has been developed for the treatment of excess bone resorption in patients with osteoporosis and certain cancers. PTH also inhibits the production and secretion of sclerostin from osteocytes. Sclerostin is one of several proteins that blocks osteoblast proliferation by inhibiting the wnt pathway. Thus, PTH indirectly increases proliferation of osteoblasts, the cells responsible for bone formation. An antibody against sclerostin is in clinical trials for the treatment of osteoporosis. Although both bone resorption and bone formation are enhanced by PTH, the net effect of excess endogenous PTH is to increase bone resorption. However, administration of exogenous PTH in low and intermittent doses increases bone formation without first stimulating bone resorption. This net anabolic action may be indirect, involving other growth factors such as insulin-like growth factor 1 (IGF-1) as well as inhibition of sclerostin as noted above. These anabolic actions have led to the approval of recombinant PTH 1-34 (teriparatide) for the treatment of osteoporosis. In the kidney, PTH increases tubular reabsorption of calcium and magnesium but reduces reabsorption of phosphate, amino acids, bicarbonate, sodium, chloride, and sulfate. As noted earlier another important action of PTH on the kidney is stimulation of 1,25(OH)2D production.


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 and other foods. Both the natural form (vitamin D3, cholecalciferol) and the plant-derived form (vitamin D2, ergocalciferol) are present in the diet. As discussed earlier these forms differ in that ergocalciferol contains a double bond and an additional methyl group in the side chain (Figure 42–3). Ergocalciferol and its metabolites bind less well than cholecalciferol and its metabolites to vitamin D-binding protein (DBP), the major transport protein of these compounds in blood, and have a different path of catabolism. As a result their half-lives are shorter than those of the cholecalciferol metabolites. This influences treatment strategies, as will be discussed. However, the key steps in metabolism and biologic activities of the active metabolites are comparable, so with this exception the following comments apply equally well to both forms of vitamin D.

Vitamin D is a precursor to a number of biologically active metabolites (Figure 42–3). Vitamin D is first hydroxylated in the liver and other tissues to form 25(OH)D(calcifediol). As noted earlier there are a number of enzymes with 25-hydroxylase activity. This metabolite is further converted in the kidney to a number of other forms, the best studied of which are 1,25(OH)2D (calcitriol) and 24,25-dihydroxyvitamin D (24,25[OH]2D), by the enzymes CYP27B1 and CYP24A1, respectively. The regulation of vitamin D metabolism is complex, involving calcium, phosphate, and a variety of hormones, the most important of which are PTH, which stimulates, and FGF23, which inhibits the production of 1,25(OH)2D by the kidney while reciprocally inhibiting or promoting the production of 24,25(OH)2D. The importance of CYP24A1, the enzyme that 24-hydroxylates 25(OH)D and 1,25(OH)2D, is well demonstrated in children lacking this enzyme who have high levels of calcium and 1,25(OH)2D resulting in kidney damage from nephrocalcinosis and stones. Of the natural metabolites, only vitamin D and 1,25(OH)2D (as calcitriol) are available for clinical use (Table 42–1). A number of analogs of 1,25(OH)2D have been 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 (see Chapter 61). Doxercalciferol and paricalcitol are approved for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease. Eldecalcitol is in phase 3 clinical trials in Japan for the treatment of osteoporosis. Other analogs are being investigated for the treatment of various malignancies.

TABLE 42–1 Vitamin D and its major metabolites and analogs.


Vitamin D and its metabolites circulate in plasma tightly bound to the DBP. This α-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. There is increasing evidence that it is the free or unbound forms of these metabolites that have biologic activity. This is of clinical importance because there are several different forms of DBP in the population with different affinities for the vitamin D metabolites. Such individuals vary with respect to the fraction of free metabolite available. Moreover, as noted above, the affinity of DBP for the D2 metabolites is less than that for the D3 metabolites. In normal subjects, the terminal half-life of injected calcifediol (25[OH]D) is around 23 days, whereas in anephric subjects it is around 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 (1,25[OH]2D) in humans likewise indicates a rapid turnover, with a terminal half-life measured in hours. Several of the 1,25(OH)2D analogs are bound poorly by DBP. As a result, their clearance is very rapid, with a terminal half-life of minutes. Such analogs have less hypercalcemic, hypercalciuric effects than calcitriol, an important aspect of their use in the management of conditions such as psoriasis and hyperparathyroidism.

The mechanism of action of the vitamin D metabolites remains under active investigation. However, 1,25(OH)2D is well established as the most potent stimulant of intestinal calcium and phosphate transport and bone resorption. 1,25(OH)2D 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 process that does not require new protein synthesis. The molecular action of 1,25(OH)2D on bone has received less attention. However, like PTH, 1,25(OH)2D can induce RANKL 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.

Specific receptors for 1,25(OH)2D (VDR) exist in nearly all tissues, not just intestine, bone, and kidney; as a result much effort has been made to develop analogs of 1,25(OH)2D that will target these non-classic tissues without increasing serum calcium. These non-classic actions include regulation of the secretion of PTH, insulin, and renin; dendritic cell as well as T-cell differentiation; and proliferation and differentiation of a number of cancer cells. Thus, the clinical utility of 1,25(OH)2D and its analogs is expanding.


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)2D production and phosphate reabsorption (via the sodium phosphate co-transporters NaPi 2a and 2c) in the kidney, and can lead to both hypophosphatemia and inappropriately low levels of circulating 1,25(OH)2D. Whereas FGF23 was originally identified in certain mesenchymal tumors, osteoblasts and osteocytes in bone appear to be its primary site of production. Other tissues can also 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 abnormal deposition of calcium phosphate in periarticular tissues (tumoral calcinosis) with elevated phosphate and 1,25(OH)2D. FGF23 is normally inactivated by cleavage at an RXXR site (amino acids 176–179). Mutations in this site lead to excess FGF23, the underlying problem in autosomal dominant hypophosphatemic rickets. A 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, and the mechanism by which PHEX mutations lead to increased FGF23 levels remains obscure. FGF23 binds to FGF receptors 1 and 3c 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)2D levels, a phenotype quite similar to inactivating mutations in FGF23 or GALNT3. FGF23 production is stimulated by 1,25(OH)2D and phosphate and directly or indirectly inhibited by the dentin matrix protein DMP1 found in osteocytes. Mutations in DMP1 lead to increased FGF23 levels and osteomalacia.


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 important feedback loops. Calcium is one of two principal regulators of PTH secretion. It binds to a novel ion recognition site that is part of a Gq protein-coupled receptor called the calcium-sensing receptor (CaSR) that employs the phosphoinositide second messenger system to link changes in the extracellular calcium concentration to changes in the intracellular free calcium. As serum calcium levels rise and activate this receptor, intracellular calcium levels increase and inhibit PTH secretion. This inhibition by calcium of PTH secretion, along with inhibition of renin and atrial natriuretic peptide secretion, is the opposite of the effect in other tissues such as the beta cell of the pancreas, in which calcium stimulates secretion. Phosphate regulates PTH secretion directly and indirectly by forming complexes with calcium in the serum. Because it is the ionized free concentration of extracellular calcium that is detected by the parathyroid gland, increases in serum phosphate levels reduce the ionized calcium, leading 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.

TABLE 42–2 Actions of parathyroid hormone (PTH), vitamin D, and FGF23 on gut, bone, and kidney.


High serum calcium works directly and indirectly by reducing PTH secretion. High serum 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 directly inhibits PTH secretion (independent of its effect on serum calcium) by a direct inhibitory effect on PTH gene transcription. This provides yet another negative feedback loop. In patients with chronic renal failure who frequently are deficient in producing 1,25(OH)2D, loss of this 1,25(OH)2D-mediated feedback loop coupled with impaired phosphate excretion and intestinal calcium absorption leads to secondary hyperparathyroidism. The ability of 1,25(OH)2D to inhibit PTH secretion directly is being exploited with 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)2D also stimulates the production of FGF23. This completes the negative feedback loop in that FGF23 inhibits 1,25(OH)2D production while promoting hypophosphatemia, which in turn inhibits FGF23 production and stimulates 1,25(OH)2D production.


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, several of these hormones, including calcitonin, glucocorticoids, and estrogens, have actions on bone mineral homeostatic mechanisms that can be exploited therapeutically.


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 chemical heterogeneity, calcitonin preparations are 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. Salmon calcitonin has a longer half-life of 40–50 minutes, making it more attractive as a therapeutic agent. Much of the clearance occurs in the kidney by metabolism; 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 relationship 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, albeit a less efficacious drug than other available agents.


Glucocorticoid hormones alter bone mineral homeostasis by antagonizing vitamin D-stimulated intestinal calcium transport, stimulating renal calcium excretion, and 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 unregulated ectopic production of 1,25[OH]2D occurs) or in cases of vitamin D intoxication. Prolonged administration of glucocorticoids is a common cause of osteoporosis in adults and can cause stunted skeletal development in children.


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

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. However, estrogens also increase DBP production by the liver, which increases the total concentrations of the vitamin D metabolites in circulation without necessarily increasing the free levels. Estrogen receptors have been found in bone, and estrogen has direct effects on bone remodeling. 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 has fallen out of favor due to concern about adverse effects. Selective estrogen receptor modulators (SERMs) have been developed to retain the beneficial effects on bone while minimizing deleterious effects on breast, uterus, and the cardiovascular system (see Box: Newer Therapies for Osteoporosis and Chapter 40).



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). Currently available bisphosphonates include etidronate, pamidronate, alendronate, risedronate, tiludronate, ibandronate, and zoledronate. With the development of the more potent bisphosphonates, etidronate is seldom used.


FIGURE 42–4 The structure of pyrophosphate and of the first three bisphosphonates—etidronate, pamidronate, and alendronate—that were approved for use in the USA.

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. A major adverse effect of oral forms of the bisphosphonates (risedronate, alendronate, ibandronate) is esophageal and gastric irritation, which limits the use of this route by patients with upper gastrointestinal disorders. This complication can be circumvented with infusions of pamidronate, zoledronate, and ibandronate. Intravenous dosing also allows a larger amount of drug to enter the body and markedly reduces the frequency of administration (eg, zoledronate is infused once per year). Nearly half of the absorbed drug accumulates in bone; the remainder is excreted unchanged in the urine. Decreased renal function dictates a reduction in dosage. The portion of drug retained in bone depends on the rate of bone turnover; drug in bone often is retained for months to years.

Newer Therapies for Osteoporosis

Bone undergoes a continuous remodeling process involving resorption and formation. Any process that disrupts this balance by increasing bone resorption relative to formation results in osteoporosis. Inadequate gonadal hormone production is a major cause of osteoporosis in men and women. Estrogen replacement therapy at menopause is a well-established means of preventing osteoporosis in the female, but many women fear its adverse effects, particularly the increased risk of breast cancer from continued estrogen use (the well-demonstrated increased risk of endometrial cancer is prevented by combining the estrogen with a progestin) and do not like the persistence of menstrual bleeding that often accompanies this form of therapy. Medical enthusiasm for this treatment has waned with the demonstration that it does not protect against and may increase the risk of heart disease. Raloxifene was the first of the selective estrogen receptor modulators (SERMs; see Chapter 40) to be approved for the prevention of osteoporosis. Raloxifene shares some of the beneficial effects of estrogen on bone without increasing the risk of breast or endometrial cancer (it may actually reduce the risk of breast cancer). Although not as effective as estrogen in increasing bone density, raloxifene has been shown to reduce vertebral fractures.

Nonhormonal forms of therapy for osteoporosis have been developed with proven efficacy in reducing fracture risk. Bisphosphonates such as alendronate, risedronate, and ibandronate have been conclusively shown to increase bone density and reduce fractures over at least 5 years when used continuously at a dosage of 10 mg/d or 70 mg/wk for alendronate; 5 mg/d or 35 mg/wk for risedronate; 2.5 mg/d or 150 mg/month for ibandronate; and 5 mg annually for intravenous zoledronate. Side-by-side trials between alendronate and calcitonin (another approved nonestrogen drug for osteoporosis) indicated a greater efficacy of alendronate. Bisphosphonates are poorly absorbed and must be given on an empty stomach or infused intravenously. At the higher oral doses used in the treatment of Paget’s disease, alendronate causes gastric irritation, but this is not a significant problem at the doses recommended for osteoporosis when patients are instructed to take the drug with a glass of water and remain upright. Denosumab is a human monoclonal antibody directed against RANKL, and is very effective in inhibiting osteoclastogenesis and activity. Denosumab is given in 60 mg doses subcutaneously every 6 months. All of these drugs inhibit bone resorption with secondary effects to inhibit bone formation. On the other hand, teriparatide, the recombinant form of PTH 1-34, directly stimulates bone formation as well as bone resorption. However, teriparatide is given daily by subcutaneous injection. Its efficacy in preventing fractures is at least as great as that of the bisphosphonates. In all cases, adequate intake of calcium and vitamin D needs to be maintained.

Furthermore, there are several other forms of therapy in development. In Europe, strontium ranelate, a drug that appears to stimulate bone formation and inhibit bone resorption, has been used for several years with favorable results in large clinical trials; approval for use in the USA is expected. Additional promising new treatments undergoing clinical trials include an antibody against sclerostin, that has been shown to stimulate bone formation, and inhibitors of cathepsin K, an enzyme in osteoclasts that facilitates bone resorption. In Japan, eldecalcitol, an analog of 1,25(OH)2D, is showing promise for the treatment of osteoporosis with minimal effects on serum calcium.

The bisphosphonates exert multiple effects on bone mineral homeostasis, which make them useful for the treatment of hypercalcemia associated with malignancy, for Paget’s disease, and for osteoporosis (see Box: Newer Therapies for Osteoporosis). They 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. 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 slowing bone resorption. This may be due to their other cellular effects, which include 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 activity.

Amino bisphosphonates such as alendronate and risedronate inhibit farnesyl pyrophosphate synthase, an enzyme in the mevalonate pathway that appears to be critical for osteoclast survival. The cholesterol-lowering statin drugs (eg, lovastatin), which block mevalonate synthesis (see Chapter 35), 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. The mevalonate pathway effects vary depending on the bisphosphonate used (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.

With the exception of the induction of a mineralization defect by higher than approved doses of etidronate and gastric and esophageal irritation by the oral bisphosphonates, 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 or by using the intravenous forms of these compounds. Of the other complications, osteonecrosis of the jaw has received considerable attention but is rare in patients receiving usual doses of bisphosphonates (perhaps 1/100,000 patient-years). This complication is more frequent when high intravenous doses of zoledronate are used to control bone metastases and cancer-induced hypercalcemia. More recently, concern has been raised about over-suppressing bone turnover. This may underlie the occurrence of subtrochanteric femur fractures in patients on long-term bisphosphonate treatment. This complication appears to be rare, comparable to that of osteonecrosis of the jaw, but has led some authorities to recommend a “drug holiday” after 5 years of treatment if the clinical condition warrants it (ie, if the fracture risk of discontinuing the bisphosphonate is not deemed high).


Denosumab is a fully human monoclonal antibody that binds to and prevents the action of RANKL. As described earlier, RANKL is produced by osteoblasts and other cells, including T lymphocytes. It stimulates osteoclastogenesis via RANK, the receptor for RANKL that is present on osteoclasts and osteoclast precursors. By interfering with RANKL function, denosumab inhibits osteoclast formation and activity. It is at least as effective as the potent bisphosphonates in inhibiting bone resorption and has been approved for treatment of postmenopausal osteoporosis and some cancers (prostate and breast). The latter application is to limit the development of bone metastases or bone loss resulting from the use of drugs that suppress gonadal function. Denosumab is administered subcutaneously every 6 months. The drug appears to be well tolerated but three concerns remain. First, a number of cells in the immune system also express RANKL, suggesting that there could be an increased risk of infection associated with the use of denosumab. Second, because the suppression of bone turnover with denosumab is similar to that of the potent bisphosphonates, the risk of osteonecrosis of the jaw and subtrochanteric fractures may be increased, although this has not been reported in the clinical trials leading to its approval by the FDA. Third, denosumab can lead to transient hypocalcemia, especially in patients with marked bone loss (and bone hunger) or compromised calcium regulatory mechanisms, including chronic kidney disease and vitamin D deficiency.


Cinacalcet is the first representative of a new class of drugs that activates the calcium-sensing receptor (CaSR) described above. CaSR is widely distributed but has its greatest concentration in the parathyroid gland. By activating the parathyroid gland CaSR, cinacalcet inhibits PTH secretion. Cinacalcet is approved for the treatment of secondary hyperparathyroidism in chronic kidney disease and for the treatment of parathyroid carcinoma. CaSR antagonists are also being developed, and may be useful in conditions of hypoparathyroidism or as a means to stimulate intermittent PTH secretion in the treatment of osteoporosis.


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 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 amount required to achieve cytotoxic effects. With the development of other less toxic drugs for these purposes, the clinical use of plicamycin is seldom indicated.


The chemistry and pharmacology of the thiazide family of drugs are discussed 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 (see Figure 15–4). Thiazides have proved to be useful in reducing the hypercalciuria and incidence of urinary 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 is well established as effective for the prophylaxis of dental caries and has previously been investigated 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 accumulates in 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 its ability to promote 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. Despite these promising effects of fluoride on bone mass, clinical studies have failed to demonstrate a reliable reduction in fractures, and some studies showed an increase in fracture rate. At present, fluoride is not approved by the FDA for treatment or prevention of osteoporosis, and it is unlikely to be.

Adverse effects observed—at the higher 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).


Strontium ranelate is composed of two atoms of strontium bound to an organic ion, ranelic acid. Although not yet approved for use in the USA, this drug is used in Europe for the treatment of osteoporosis. Strontium ranelate appears to block differentiation of osteoclasts while promoting their apoptosis, thus inhibiting bone resorption. At the same time, strontium ranelate appears to promote bone formation. Unlike bisphosphonates, denosumab, 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.


Individuals with disorders of bone mineral homeostasis usually 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, osteocalcin, and N- and C-terminal propeptides of type I collagen (reflecting osteoblastic activity), and serum and urine levels of tartrate-resistant acid phosphatase and collagen breakdown products (reflecting osteoclastic activity). The kidney becomes involved when the calcium × phosphate product in serum rises above the point at which ectopic calcification occurs (nephrocalcinosis) or when the calcium × 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.



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 use of the drug for this purpose 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 enhances urine flow and also inhibits calcium reabsorption in the ascending limb of the loop of Henle (see Chapter 15). Monitoring of 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 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).


Pamidronate, 60–90 mg, infused over 2–4 hours, and zoledronate, 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 bisphosphonate 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 initial infusion, but subsequent infusions generally do not have this side effect. Repeated doses of these drugs have been linked to renal deterioration and osteonecrosis of the jaw, but this adverse effect is rare.


Calcitonin has proved useful as ancillary treatment in some 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 inhibits 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 of plicamycin 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.


Intravenous phosphate administration 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 salts. Amounts required to provide 1 g of elemental phosphorus are as follows:


In-Phos, 40 mL; or Hyper-Phos-K, 15 mL


Fleet Phospho-Soda, 6.2 mL; or Neutra-Phos, 300 mL; or K-Phos-Neutral, 4 tablets


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 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 and increase renal excretion of calcium. 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.


The main features of hypocalcemia are neuromuscular—tetany, paresthesias, laryngospasm, muscle cramps, and seizures. The major causes of hypocalcemia in the adult are hypoparathyroidism, vitamin D deficiency, chronic kidney disease, and malabsorption. Hypocalcemia can also accompany the infusion of potent bisphosphonates and denosumab for the treatment of osteoporosis, but this is seldom of clinical significance unless the patient is already hypocalcemic at the onset of the infusion. 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 investigation. Large infusions of citrated blood can produce hypocalcemia secondary to the formation of citrate-calcium complexes. Calcium and vitamin D (or its metabolites) form the mainstay of treatment of hypocalcemia.


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 preferred 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 × 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 is a common complication of renal failure and is also found in all types of hypoparathyroidism (idiopathic, surgical, and pseudohypoparathyroidism), vitamin D intoxication, and the rare syndrome of tumoral calcinosis (usually due to insufficient bioactive FGF23). 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 phosphate-binding gels such as sevelamer, or lanthanum carbonate and 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. In patients with chronic kidney disease enthusiasm for the use of large doses of calcium to control hyperphosphatemia has waned because of the risk of ectopic calcification.


Hypophosphatemia is associated with a variety of conditions, including primary hyperparathyroidism, vitamin D deficiency, idiopathic hypercalciuria, conditions associated with increased bioactive FGF23 (eg, X-linked and autosomal dominant hypophosphatemic rickets and tumor-induced osteomalacia), 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 cause 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 include proximal muscle weakness and abnormal bone mineralization (osteomalacia). Therefore, hypophosphatemia should be avoided when using forms of therapy that can lead to it (eg, phosphate binders, certain types of parenteral nutrition) and treated in conditions that cause it, such as the various forms of hypophosphatemic rickets. Oral forms of phosphate are listed above.



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 and cost effective, medical management of this disease will need to be reconsidered. Primary hyperparathyroidism is often associated with low levels of 25(OH)D, suggesting that mild vitamin D deficiency may be contributing to the elevated PTH levels. Vitamin D supplementation in such situations has proved safe with respect to further elevations of serum and urine calcium levels, but calcium should be monitored nevertheless when vitamin D is provided.


In PTH deficiency (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 goal is to restore normocalcemia and normophosphatemia. Vitamin D (either D2 or D3; 25,000–100,000 IU three times per week) and dietary calcium supplements have been used in the past. More rapid increments in serum calcium can be achieved with calcitriol. Many patients treated with vitamin D experience episodes of hypercalcemia and hypercalciuria. This complication is more rapidly reversible with cessation of calcitriol therapy than therapy with vitamin D. This would be of importance to the patient in whom such hypercalcemic crises are common. Full-length PTH (Natpara) has been developed for the treatment of hypoparathyroidism and has been shown in phase 3 trials to reduce the need for large doses of calcium and calcitriol with less risk of hypercalciuria. It is currently being evaluated by the FDA for this condition.


The level of vitamin D thought to be necessary for good health is being reexamined with the appreciation that vitamin D acts on a large number of cell types beyond those responsible for bone and mineral metabolism. 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 20–30 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. An expert panel for the Institute of Medicine (IOM) has recently recommended that a level of 20 ng/mL (50 nM) was sufficient, although up to 50 ng/mL (125 nM) was considered safe. For individuals between the ages of 1 and 70 years, 600 IU/d vitamin D was thought to be sufficient to meet these goals, although up to 4000 IU was considered safe. These recommendations are based primarily on data from randomized placebo-controlled clinical trials (RCT) that evaluated falls and fractures; data supporting the nonskeletal effects of vitamin D were considered too preliminary to be used in their recommendations because of lack of RCT for these other actions. The lower end of these recommendations has been considered too low and the upper end too restrictive by a number of vitamin D experts, and the Endocrine Society has published a different set of recommendations suggesting that 30 ng/mL was a more appropriate lower limit. Nevertheless, the call for better clinical data from RCTs, especially for the nonskeletal actions, is appropriate. The IOM guidelines—at least with respect to the lower recommended levels of vitamin D supplementation—are unlikely to correct vitamin D deficiency in individuals with obesity, dark complexions, limited capacity for sunlight exposure, or malabsorption. Vitamin D deficiency or insufficiency can be treated by higher dosages (either D2 or D3, 1000–4000 IU/d or 50,000 IU/wk for several weeks). No other vitamin D metabolite is indicated. Because the half-life of vitamin D3 metabolites in blood is greater than that of vitamin D2, there are advantages to using vitamin D3 rather than vitamin D2 supplements, although when administered on a daily or weekly schedule these differences may be moot. The diet should also contain adequate amounts of calcium as several studies indicate a synergism between calcium and vitamin D with respect to a number of their actions.


The major sequelae of chronic kidney disease that impact bone mineral homeostasis are deficient 1,25(OH)2D production, retention of phosphate with an associated reduction in ionized calcium levels, and the secondary hyperparathyroidism that results from the parathyroid gland response to lowered serum ionized calcium and low 1,25(OH)2D. FGF23 levels are also increased in this disorder in part due to the increased phosphate, and this can further reduce 1,25(OH)2D production by the kidney. Although still investigational, antibodies to FGF23 in the early stages of renal failure result in normalization of 1,25(OH)2D levels. With impaired 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 secondary 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 overzealous treatment with calcium. However, 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. 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 to treat this disorder. However, with the reduction in 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 (20–30 ng/mL) with vitamin D. 1,25(OH)2D3 (calcitriol) rapidly corrects hypocalcemia and at least partially reverses 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 in the USA for the treatment of secondary hyperparathyroidism of chronic kidney disease. (In Japan, maxacalcitol [22-oxa-calcitriol] and falecalcitriol [26,27 F6-1,25(OH)2D3] are approved for this purpose.) Their principal advantage is that they are less likely than calcitriol to induce hypercalcemia for any given reduction in PTH (less true for falecalcitriol). 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 of serum PTH and alkaline phosphatase levels is useful in determining whether therapy is correcting or preventing secondary hyperparathyroidism. In patients on dialysis, a PTH value of approximately twice the upper limits of normal is considered desirable to prevent adynamic bone disease. 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 adynamic bone disease. Unlike the rapid changes in serum values, changes in bone morphology require months to years. Monitoring of serum vitamin D metabolite levels is useful for determining adherence, absorption, and metabolism.


A number of gastrointestinal and hepatic diseases cause disordered calcium and phosphate homeostasis, which ultimately leads to bone disease. As bariatric surgery becomes more common, this problem is likely to increase. The bones in such patients show a combination of osteoporosis and osteomalacia. Osteitis fibrosa does not occur, in contrast to renal osteodystrophy. The important common feature in this group of diseases appears to be malabsorption of calcium and vitamin D. Liver disease may, in addition, reduce the production of 25(OH)D from vitamin D, although its importance in patients other than those with terminal liver failure remains in dispute. The malabsorption of vitamin D is probably not limited to exogenous vitamin D as the liver secretes into bile a substantial number of vitamin D metabolites and conjugates that are normally reabsorbed in (presumably) the distal jejunum and ileum. Interference with this process could deplete the body of endogenous vitamin D metabolites in addition to limiting absorption of dietary vitamin D.

In mild forms of malabsorption, high doses of vitamin D (25,000–50,000 IU 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. However, calcifediol is no longer available in the USA. Both calcitriol and 24,25(OH)2D may be of importance in reversing the bone disease. Intramuscular injections of vitamin D would be an alternative form of therapy, but there are currently no FDA-approved intramuscular preparations available in the USA. The skin remains a good source of vitamin D production, although care is needed to prevent UVB overexposure (ie, by avoiding sunburn) to reduce the risk of photoaging and skin cancer.

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 is defined as abnormal loss of bone predisposing to fractures. It is most common in postmenopausal women but also occurs in men. The annual direct medical cost of fractures in older women and men in the USA is estimated to be at least 20 billion dollars per year, and is increasing as our population ages. Osteoporosis is most commonly associated with loss of gonadal function as in menopause but may also occur as an adverse effect of long-term administration of glucocorticoids or other drugs, including those that inhibit sex steroid production; 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 reduced estrogen production and can be treated with estrogen (combined 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 or may actually increase the development of heart disease has reduced enthusiasm for this form of therapy, at least in older individuals.


FIGURE 42–5 Typical changes in bone mineral density with time after the onset of menopause, with and without treatment. In the untreated condition, bone is lost during aging in both men and women. Strontium (Sr2+), parathyroid hormone (PTH), and vitamin D promote bone formation and can increase bone mineral density in subjects who respond to them throughout the period of treatment, although PTH and vitamin D in high doses also activate bone resorption. In contrast, estrogen, calcitonin, denosumab, and bisphosphonates block bone resorption. This leads to a transient increase in bone mineral density because bone formation is not initially decreased. However, with time, both bone formation and bone resorption decrease with these pure antiresorptive agents, and bone mineral density reaches a new plateau.

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, or ibandronate, 2.5 mg/d; or weekly schedules of alendronate, 70 mg/wk, or risedronate, 35 mg/wk; or monthly schedules of ibandronate, 150 mg/month; or quarterly (every 3 months) injections of ibandronate, 3 mg; or annual infusions of zoledronate, 5 mg. These drugs are effective in men as well as women and for various causes of osteoporosis.

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. The SERM raloxifene is approved for treatment of osteoporosis. Like tamoxifen, raloxifene reduces the risk of breast cancer. It protects against spine fractures but not hip fractures—unlike bisphosphonates, denosumab, and teriparatide, which protect against both. Raloxifene does not prevent hot flushes and imposes the same increased risk of venous thromboembolism as estrogen. To counter the reduced intestinal calcium transport associated with osteoporosis, vitamin D therapy is often used in combination with dietary calcium supplementation. In several large studies, vitamin D supplementation (800 IU/d) with calcium has been shown to improve bone density, reduce falls, and prevent fractures. Calcitriol and its analog, 1α(OH)D3, have also been shown to increase bone mass and reduce fractures. Use of these agents for osteoporosis is not FDA-approved, although they are used for this purpose in other countries.

Teriparatide, the recombinant form of PTH 1-34, is approved for treatment of osteoporosis. It is given in a dosage of 20 mcg subcutaneously daily. 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. The drug is approved for only 2 years of use. Trials examining the sequential use of teriparatide followed by a bisphosphonate after 1 or 2 years are in progress and look promising. Use of the drug 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.

Denosumab, the RANKL inhibitor, has recently been approved for treatment of postmenopausal osteoporosis. It is given subcutaneously every 6 months in 60 mg doses. Like the bisphosphonates it suppresses bone resorption and secondarily bone formation. Denosumab reduces the risk of both vertebral and nonvertebral fractures with comparable effectiveness to the potent bisphosphonates.

Strontium ranelate has not been approved in the USA for the treatment of osteoporosis but is being used in Europe, generally at a dose of 2 g/d.


These disorders usually manifest in childhood as rickets and hypophosphatemia, although they may first present in adults. In both X-linked and autosomal dominant hypophosphatemia, biologically active FGF23 accumulates, leading to phosphate wasting in the urine and hypophosphatemia. In autosomal dominant hypophosphatemia, mutations in the FGF23 gene replace an arginine required for proteolysis and result in increased FGF23 stability. X-linked hypophosphatemia is caused by mutations in the gene encoding the PHEX protein, an endopeptidase. Initially, it was thought that FGF23 was a direct substrate for PHEX, but this no longer appears to be the case. Tumor-induced osteomalacia is a phenotypically similar but acquired syndrome in adults that results from overexpression of FGF23 in tumor cells. The current concept for all of these diseases is that FGF23 blocks the renal uptake of phosphate and blocks 1,25(OH)2D production leading to rickets in children and osteomalacia in adults. Phosphate is critical to normal bone mineralization; when phosphate stores are deficient, a clinical and pathologic picture resembling vitamin D–dependent rickets develops. However, affected children fail to respond to the standard doses of vitamin D used in the treatment of nutritional rickets. A defect in 1,25(OH)2D production by the kidney contributes to the phenotype as 1,25(OH)2D levels are low relative to 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 these 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, although prolonged treatment often leads to secondary hyperparathyroidism.


These distinctly different autosomal recessive diseases present as childhood rickets that do not respond to conventional doses of vitamin D. Pseudovitamin D deficiency rickets is due to an isolated deficiency of 1,25(OH)2D production caused by mutations in 25(OH)-D-1α-hydroxylase (CYP27B1). This condition is treated with calcitriol (0.25–0.5 mcg daily). Hereditary vitamin D–resistant rickets (HVDRR) is caused by mutations in the gene for the vitamin D receptor. The serum levels of 1,25(OH)2D are very high in HVDRR but inappropriately low for the level of calcium in pseudovitamin D–deficient rickets. Treatment with large doses of calcitriol has been claimed to be effective in restoring normocalcemia in some HVDRR 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 rickets in some children, similar to studies in mice in which the VDR gene has been deleted. These diseases are rare.


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 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.


Individuals 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 increased 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, 100–300 mg daily, may reduce stone formation by reducing uric acid excretion.



Paget’s disease is a localized bone disorder characterized by uncontrolled osteoclastic bone resorption with secondary increases in poorly organized bone formation. The cause of Paget’s disease is obscure, although some studies suggest that a measles-related virus may be involved. The disease is fairly common, although symptomatic bone disease is less common. Recent studies indicate that this infection may produce a factor that increases the stimulation of bone resorption by 1,25(OH)2D. 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, fractures, 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/d 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 tiludronate are the bisphosphonates currently approved for clinical use in Paget’s disease of bone in the USA. 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 a bisphosphonate. 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 etidronate 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.


Patients with short bowel syndromes and associated 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 twofold: 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






Becker DJ, Kilgore ML, Morrisey MA: The societal burden of osteoporosis. Curr Rheumatol Rep 2010;12:186.

Bhattacharyya N et al: Fibroblast growth factor 23: State of the field and future directions. Trends Endocrinol Metab 2012;23:610.

Bikle DD: Nonclassic actions of vitamin D. J Clin Endocrinol Metabol 2009;94:26.

Clines GA: Mechanisms and treatment of hypercalcemia of malignancy. Curr Opin Endocrinol Diabetes Obes 2011;18:339.

Cooper C et al: Long-term treatment of osteoporosis in postmenopausal women: a review from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) and the International Osteoporosis Foundation (IOF). Curr Med Res Opin 2012;28:475.

Cummings SR et al: Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009;361:756.

Favus MJ: Bisphosphonates for osteoporosis. N Engl J Med 2010;363:2027.

Fukagawa M et al: Vitamin D supplementation in renal disease: Is calcitriol all that is needed? Scand J Clin Lab Invest Suppl 2012;243:120.

Green J, Lipton A: Anticancer properties of zoledronic acid. Cancer Invest 2010;28:944.

Hagino H: Eldecalcitol: Newly developed active vitamin D3 analog for the treatment of osteoporosis. Expert Opin Pharmacother 2013;14:817.

Holick MF: Vitamin D deficiency. N Engl J Med 2007;357:266.

Holick MF et al: Evaluation, treatment, and prevention of vitamin D deficiency: An Endocrine Sociey Clinical Practice Guideline J Clin Endocrinol Metab 2011;96:1911.

Mosekilde L et al: The pathogenesis, treatment, and prevention of osteoporosis in men. Drugs 2013;73:15.

Neer RM et al: Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001;344:1434.

Nemeth EF, Shoback D: Calcimimetic and calcilytic drugs for treating bone and mineral-related disorders. Best Pract Res Clin Endocrinol Metab 2013;27:373.

Pettifor JM: Rickets and vitamin D deficiency in children and adolescents. Endocrinol Metab Clin North Am 2005;34:537.

Qazi RA, Martin KJ: Vitamin D in kidney disease: Pathophysiology and the utility of treatment. Endocrinol Metab Clin North Am 2010;39:355.

Rizzoli R et al: Vitamin D supplementation in elderly or postmenopausal women: A 2013 update of the 2008 recommendations from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO). Curr Med Res Opin 2013;29:305.

Ross AC et al: The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: What clinicians need to know. J Clin Endocrinol Metab 2011;96:53.

Zwolak P, Dudek AZ: Antineoplastic activity of zoledronic acid and denosumab. Anticancer Res 2013;33:2981.


There are multiple reasons for this patient’s osteoporosis, including a heavy smoking history, possible alcoholism, and chronic inflammatory disease treated with glucocorticoids. High levels of cytokines from the chronic inflammation activate osteoclasts. Glucocorticoids increase urinary losses of calcium, suppress bone formation, and inhibit intestinal calcium absorption as well as decreasing gonadotropin production, leading to hypogonadism. Management should include measurement of serum testosterone, calcium, 25(OH)D, and the 24-hour urine calcium and creatinine levels (to verify completeness of collection), with treatment as appropriate for these secondary causes, plus initiation of bisphosphonate or denosumab therapy as primary treatment.



Antimicrobial agents provide some of the most dramatic examples of the advances of modern medicine. Many infectious diseases once considered incurable and lethal are now amenable to treatment with a few doses of antibiotics. The remarkably powerful and specific activity of antimicrobial drugs is due to their selectivity for targets that are either unique to prokaryote and fungal microorganisms or much more important in these organisms than in humans. Among these targets are bacterial and fungal cell wall-synthesizing enzymes (Chapters 43 and 48), the bacterial ribosome (Chapters 44 and 45), the enzymes required for nucleotide synthesis and DNA replication (Chapter 46), and the machinery of viral replication (Chapter 49). The special group of drugs used in mycobacterial infections is discussed in Chapter 47. The cytotoxic antiseptics and disinfectants are discussed in Chapter 50. The clinical uses of many antimicrobial agents are reviewed in Chapter 51.

The major problem threatening the continued success of antimicrobial drugs is the development of resistant organisms. Bacteria “invented” antibiotics billions of years ago, and resistance is primarily the result of bacterial adaptation to antibiotic exposure over millennia. Antibiotic resistance mechanisms existed before the clinical use of antibiotics, even to synthetic drugs that were created in the 20th century. Since resistance mechanisms are already present in nature, an inevitable consequence of antimicrobial use is the selection of resistant microorganisms, one of the clearest examples of evolution in action. Over the last 70 years, antibiotic use in patients and animals has fueled a major increase in the prevalence of drug-resistant pathogens. In recent years, highly resistant gram-negative organisms with novel mechanisms of resistance have been increasingly reported. Some of these strains have spread over vast geographic areas as a result of patients seeking medical care in different countries.

Much attention has been focused on eliminating the misuse of antibiotics to slow the tide of resistance. Antibiotics are misused in a variety of ways, including use in patients who are unlikely to have bacterial infections, use over unnecessarily prolonged periods, and use of multiple agents or broad-spectrum agents when not needed. Large quantities of antibiotics have been used in agriculture to stimulate growth and prevent infection in livestock, and this has added to the selection pressure that results in resistant organisms. In December 2013, the FDA announced a program to phase out the nontherapeutic use of antibiotics in livestock. However, even if this program is successful, it will take years before the benefits are apparent.

Antibiotic resistance has many negative consequences. The prevalence of resistant organisms drives the use of broader-spectrum, less efficacious, or more toxic antibiotics. Not surprisingly, infections caused by antibiotic-resistant pathogens are associated with increased costs, morbidity, and mortality. Each year in the United States, at least 2 million people acquire serious infections with resistant bacteria. At least 23,000 people die each year as a direct result of these antibiotic-resistant infections. The total economic cost of antibiotic resistance to the US economy has been difficult to calculate. Estimates vary but have ranged as high as $20 billion in excess direct healthcare costs.

Unfortunately, as the need has grown in recent years, development of novel antibiotics has slowed. Several of the largest pharmaceutical companies have abandoned research and development in this area because of diminished success and profits; the resulting reduction in new drug introductions is shown in the figure below, which shows new systemic antibacterial agents approved by the FDA per 5-year period through 2012. The most vulnerable molecular targets of antimicrobial drugs have been identified and, in many cases, crystallized and characterized. Pending the identification of new targets and compounds, it seems likely that over the next decade we will have to rely on currently available families of drugs. In the face of continuing development of resistance, considerable effort will be required to maintain the effectiveness of these drug groups.


Decline in the number of new systemic antibacterial drugs approved by the FDA over a 30-year period. (Reproduced, with permission, from Boucher HW et al: 10 × ‵20 progress -- development of new drugs active against gram-negative bacilli: An update from the Infectious Diseases Society of America. Clin Infect Dis 2013;56:1685. By permission of Oxford University Press on behalf of the Infectious Diseases Society of America. Modified, with permission, from Spellberg B et al: Trends in antimicrobial drug development: Implications for the future. Clin Infect Dis 2004;38:1279. By permission of Oxford University Press.)