Brody's Human Pharmacology: With STUDENT CONSULT

Chapter 44 Calcium-Regulating Hormones and Other Agents Affecting Bone


Agents that promote Ca++ and bone resorption

Vitamin D, metabolites, and analogs

Parathyroid hormone and analogs

Agents that inhibit Ca++ and bone resorption



Estrogens and SERMs

Therapeutic Overview

The plasma Ca++ concentration is normally maintained within narrow limits of 8.5 to 10.4 mg/dL. Approximately 45% of the plasma Ca++ (~ 2 mM) is bound to plasma proteins and fatty acid anionic groups, and approximately 10% is complexed with inorganic anions. Intracellular Ca++ (200 nM) is maintained by low membrane permeability to passive Ca++ transport and exists unbound or stored in the mitochondria and endoplasmic (sarcomella) reticulum. When ionized Ca++ levels fall outside the normal physiological range, compensatory mechanisms occur. Failure to restore normal levels adversely affects cellular and whole body physiology. Calcium levels less than 8.5 mg/dL are indicative of hypocalcemia, which can lead to increased neuromuscular excitability and tetany and impairment of mineralization of the skeleton. Calcium levels exceeding 10.5 mg/dL are indicative of hypercalcemia and can precipitate life-threatening cardiac dysrhythmias, soft tissue calcification (e.g., kidney stones), and central nervous system abnormalities.

The primary sites of regulation of Ca++ levels are the kidney, gastrointestinal (GI) tract, and bone (Fig. 44-1). The GI tract can normally absorb 10% to 20% of dietary Ca++, and effectiveness is directly dependent on vitamin D levels. Renal tubular reabsorption is highly efficient (99%) and recovers 10 to 20 gm of Ca++ filtered per day. Skeletal bone is the major site of Ca++ storage, containing approximately 1 kg in a 70-kg human. Of this, more than 99% is normally in a stable state, and 1% is in an exchangeable pool that turns over at a rate of approximately 20 g of Ca++ per day.


FIGURE 44–1 Sites of Ca++ regulation. Bone is the primary storage site, containing approximately 1 kg of Ca++.

The loss of normal bone structure and integrity can result from drugs, disease, or nutritional deprivation. Among diseases affecting bone integrity are disorders of Ca++ metabolism and bone diseases, which are associated with increased morbidity and mortality associated with fractures. Pharmacological treatments of diseases



Ethylenediamine tetraacetic acid






Parathyroid hormone


Receptor activator of nuclear factor-κB


Receptor activator of nuclear factor-κB ligand


Selective estrogen receptor modulator

associated with Ca++ or bone metabolism are dependent on the cause and severity of the disease and are summarized in the Therapeutic Overview Box (See page 501).

Hypocalcemia commonly results from the onset of hypoparathyroidism (low levels of parathyroid hormone, PTH) or pseudohypoparathyroidism (resistance to PTH). Regardless of the cause, the resulting imbalances of Ca++ metabolism are predictable and include increased renal excretion of Ca++, decreased formation of calcitriol (1,25-dihydroxyvitamin D, the hormonally active form of vitamin D), decreased bone resorption, and/or decreased intestinal absorption of Ca++. Therapeutic strategies include supplementation with Ca++ salts or Ca++ gluconate, the most appropriate form of vitamin D, or both. The selection of a vitamin D preparation depends on the effective production of calcitriol, which is dependent on adequate levels of PTH. For hypocalcemia resulting from decreased PTH synthesis as a consequence of Mg++ deficiency, Mg++ sulfate is administered.

Hypercalcemia can result from a variety of diverse disorders including primary hyperparathyroidism, hyperparathyroidism caused by chronic renal disease, PTH-secreting parathyroid carcinoma, PTH-related protein producing-malignancy (bronchogenic carcinoma), and bone-wasting neoplasia. Management of mild hypercalcemia (10.5 to 11.4 mg/dL) usually involves dietary restriction of Ca++ and maintenance of hydration. Moderate hypercalcemia (11.5 to 14 mg/dL) has the same considerations as the mild form but requires a more aggressive and timely management plan. Specifically, it is necessary to rapidly reduce blood Ca++ levels using saline infusion and a diuretic, if renal function is intact, or dialysis, if renal function is impaired. The loop diuretics such as furosemide increase both Ca++ and Na+excretion (see Chapter 21). Severe hypercalcemia (> 14 mg/dL) is a life-threatening condition often involving serious bone or renal pathology and requires immediate and intensive treatment. High Ca++levels, dehydration, and volume depletion must be addressed. To rapidly reduce Ca++, intravenous administration of bisphosphonates with or without calcitonin is the safest option. Other agents and approaches have been used but are associated with frequent and severe side effects that reduce their desirability.

Disorders of bone turnover, which are not usually associated with abnormal serum Ca++ and PO4−3 concentrations, are also amenable to therapy. Rickets (inadequate bone mineralization during development) or osteomalacia (inadequate bone mineralization in adults) can result from inadequate dietary intake or in situ formation of vitamin D or its active metabolite, calcitriol, or resistance to the action of these hormones. Treatment of these disorders involves administration of vitamin D, Ca++, or both. Again, the form of vitamin D chosen will depend on the ability to make calcitriol and, as needed, PO4−3.

Paget’s disease of bone is characterized by excessive bone resorption and formation, leading to areas of structurally abnormal bone microstructure (Pagetic or sclerotic bone), which appear more radiopaque than normal bone. Although the milder form is usually asymptomatic, the more severe forms can be characterized by skeletal deformities that are painful and can lead to deficits such as spinal cord depression, thickening of long bones, osteoarthritic changes in joints, skull thickening, and hearing impairment. Treatment strategies include the use of agents to decrease bone resorption and facilitate more normal bone formation such as calcitonin, the bisphosphonates, or estrogen and the selective estrogen receptor modulators (SERMs); Ca++ and vitamin D may also be included.

Osteopenia and osteoporosis are skeletal disorders characterized by compromised bone strength predisposing to an increased risk of fracture. Indicators for development include decreased estrogen levels in women and men, low initial skeletal bone thickness, small stature, family or personal history of osteopenia or osteoporosis, chronic hyperparathyroidism, sustained immunosuppression with adrenocorticosteroids, or periods of immobility. The diagnosis of osteopenia or osteoporosis is made by measuring bone mineral density as determined by scans of multiple regions of the skeleton. Therapeutic interventions are dictated by the severity of bone mineral density losses and include both nonpharmacological and pharmacological approaches. For the former, weight-bearing and muscle-strengthening exercises within tolerance and reduction of situations with high risk of falling are recommended. Pharmacological management includes administration of Ca++ or vitamin D, antiresorptive agents, and bone anabolic agents. Over-the-counter Ca++ salts (lactate, carbonate, gluconate, or citrate) that provide 1 to 1.5 g Ca++/day are recommended. A split dose of 3 × 500 mg/day reduces side effects and improves absorption. Antiresorptive agents, which interfere with osteopenia or osteoporosis by reducing bone resorption mediated by osteoclasts, include calcitonin, bisphosphonates, and SERMs. One anabolic agent, teriparatide, is approved for promoting new bone growth.

Therapeutic Overview



Hypoparathyroidism; pseudohypoparathyroidism; renal failure; inadequate calcium intake or absorption; abnormal vitamin D metabolism, ingestion, or absorption; tissue resistance


Soluble Ca++ salts and/or vitamin D or its analogs



Hyperparathyroidism, hypervitaminosis D, neoplasia, sarcoidosis, hyperthyroidism

Management (based on cause and severity):

Mild hypercalcemia: dietary restriction of calcium

Moderate hypercalcemia: loop diuretics and intravenous saline

Severe hypercalcemia: intravenous bisphosphonates, replace phosphate as needed, calcitonin, glucocorticoids

Abnormal Bone Remodeling


Paget’s disease of bone, rickets (osteomalacia), drug-induced, osteopenia, osteoporosis


Oral/intravenous bisphosphonates, calcitonin, Ca++, vitamin D, selective estrogen receptor modulators (SERMs) teriparatide

Mechanisms of Action

Vitamin D, Metabolites, and Analogs

The structure and metabolism of vitamin D is shown in Figure 44-2. Vitamin D is a secosteroid, a steroid in which the B ring is cleaved and the A ring rotated. Vitamin D3, cholecalciferol, is the natural form of vitamin D in humans and is synthesized from cholesterol in the skin in response to solar ultraviolet light. Vitamin D2, ergocalciferol, is the plant-derived form of vitamin D; both vitamins D2 and D3are present in the diet and equally effective in adults. The activation of vitamin D requires enzymatic hydroxylation by the liver and the kidney. In the endoplasmic reticulum and mitochondria of the liver, vitamin D is hydroxylated to form 25-hydroxyvitamin D (calcifediol), which becomes the primary circulating metabolite. Renal metabolism of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D (calcitriol) involves mitochondrial P450-catalyzed hydroxylation by the enzyme 1α-hydroxylase (CYP27B1), whose activity is stimulated by PTH and low plasma PO4 concentrations.


FIGURE 44–2 Sources, structure, and metabolism of vitamin D.

Calcitriol and active vitamin D analogs bind primarily to nuclear receptors in target cells and act as ligand-activated transcription factors by binding to response elements on genes and modulating synthesis of specific proteins. Among the protein products resulting from actions of vitamin D on the intestine are two high-affinity Ca++-binding proteins, the calbindins, which play a role in stimulation of intestinal Ca++ transport. Vitamin D metabolites increase absorption of dietary Ca++ and PO4−3 by stimulating uptake across the GI mucosa, leading to an increase in serum Ca++ concentration (Fig. 44-3). The antirachitic effect of vitamin D on bone mineralization is an indirect result of this increased Ca++ and PO4−3 absorption, which also results in deposition of more mineral in bone.


FIGURE 44–3 Mechanism of the antirachitic effect of 1,25-dihydroxyvitamin D. 1,25-dihydroxyvitamin D increases Ca++ and PO4−3 absorption from the intestine, increasing serum concentrations. The ions deposit in bone, increasing bone mineralization.

Vitamin D metabolites, especially at higher concentrations, stimulate the release of Ca++ from bone. The synthesis of a membrane-associated cytokine, receptor activator of nuclear factor-κB ligand(RANKL), is activated. Interaction of RANKL with receptor activator of nuclear factor-κB (RANK) receptors on osteoclasts stimulates osteoclast differentiation, survival, and activity, resulting in Ca++release (Fig. 44-4). A decoy receptor, osteoprotegerin (OPG), is produced by bone marrow stromal cells and can competitively antagonize the effects of RANKL. Increased RANKL is a general mechanism by which many factors, including PTH, prostaglandins, and inflammatory cytokines, stimulate bone resorption. Vitamin D metabolites inhibit PTH synthesis and secretion. Vitamin D also affects differentiation of other cell types, including keratinocytes.


FIGURE 44–4 Effects of 1,25-dihydroxyvitamin D, PTH, and calcitonin on osteoblast and osteoclast activity. Osteoblasts stimulate osteoclast formation, survival, and activity by a membrane-associated cytokine, RANKL, that binds to receptors (RANK) on osteoclast precursors and osteoclasts. Osteoblasts also stimulate bone formation and produce bone growth factors. Osteoclasts secrete acid and proteolytic enzymes and resorb the bone matrix. Active vitamin D metabolites and PTH increase the expression of RANKL in osteoblasts, resulting in activation of osteoclasts and resorption of bone. Calcitonin inhibits osteoclast activity via interaction with a G-protein-coupled receptor.

Several synthetic vitamin D analogs have unique clinical utility. 1α-Hydroxyvitamin D2 and dihydrotachysterol (in which the A ring is not rotated) are active even in the absence of renal 1α-hydroxylase. 19-Nor-1α, 25-hydroxyvitamin D2 (paricalcitol), and calcipotriene have less effect on Ca++ metabolism and can therefore be used for other therapeutic indications to decrease the risk of hypercalcemia. Paricalcitol is used to suppress elevated PTH secretion in chronic renal disease, and calcipotriene is used to promote normal skin cell differentiation in psoriasis.

Parathyroid Hormone

PTH is an 84-amino acid polypeptide formed from the cleavage of larger precursors in the parathyroid gland. The first 34 amino acids of PTH (PTH 1-34) possess the full effects of the peptide on bone and Ca++ metabolism. Calcium exerts negative feedback regulation of PTH secretion through a specific G-protein-linked Ca++ membrane receptor. PTH binding to target cell receptors stimulates protein phosphorylation by both protein kinase A and specific protein kinase C isozymes. PTH has multiple effects that influence Ca++ and PO4−3 metabolism and bone (Fig. 44-5). PTH acts directly at renal tubules to decrease reabsorption of PO4−3 and increase reabsorption of Ca++, resulting in decreased serum PO4−3 and increased serum Ca++ concentrations. PTH interaction with receptors on osteoblasts, analogous to vitamin D metabolites, increases production of RANKL, stimulating resorption and increasing serum Ca++ concentrations. When PTH is administered intermittently to attain subphysiological levels, an anabolic effect on bone has been reported, leading to approval by the United Sstates. Food and Drug Administration of teriparatide (recombinant human PTH 1-34), which is administered by injection to promote bone formation. This anabolic effect on bone may involve growth factors such as insulin-like growth factor-1 that promote interaction with osteoblasts. Teriparatide-injection is approved to treat severe osteoporosis for patients in whom antiresorptive agents have failed to prevent recurrent fractures. PTH enhances Ca++ absorption indirectly by stimulating the formation of 1,25-dihydroxyvitamin D (see Fig. 44-2). A recently discovered protein, the PTH-related protein, has significant amino acid sequence homology to PTH at the N-terminal region of the molecule. PTH-related protein is produced by several types of tumors, is important in malignancy-related hypercalcemias, in normal Ca++ metabolism in mammary gland and placenta, and in chondrocyte differentiation.


FIGURE 44–5 Direct and indirect effects of PTH on Ca++ metabolism. Renal tubular reabsorption of PO4−3 decreases, and that of Ca++ increases. Hormone-stimulated osteoblast activates osteoclast to release Ca++ into extracellular fluid. Intermittent stimulation of osteoblasts by PTH has anabolic effects mediated by growth factors (GFs).


Calcitonin is a 32-amino acid polypeptide secreted by the parafollicular cells of the thyroid. It decreases postprandial absorption of Ca++ and increases excretion of Ca++, Na+, Mg++, Cl, and PO4−3. At a cellular level, it inhibits the activity of osteoclasts by direct actions on G-protein-linked receptors in these cells (see Fig. 44-4). The inhibition of osteoclast activity results in a decrease in both serum Ca++and PO4−3. The ability of calcitonin to decrease hypercalcemia diminishes with continued use. Calcitonin is effective in treatment of Paget’s disease of bone and is also approved for treatment of osteoporosis. Calcitonin and the neuronal calcitonin gene-related peptide arise from differential splicing in the parafollicular cells and in neural tissue.

Estrogens and Selective Estrogen Receptor Modulators

Estrogens (see Chapter 40) inhibit bone resorption and prevent fractures. The mechanism appears to involve decreased production of interleukins that activate and promote survival of osteoclasts. Consistent with this protective effect, reduction or inhibition of estrogen production can produce osteopenia and eventually osteoporosis. These situations commonly occur as a result of ovarian failure, ovariectomy, chronic suppression with long-acting gonadotropin-releasing hormone agonists, and natural menopause. Estrogen supplementation or replacement is indicated in premenopausal women to delay the onset of osteopenia and osteoporosis. Women undergoing normal menopause have also been considered candidates for estrogen supplementation to reduce vasomotor symptoms and delay osteopenia and osteoporosis. Women with an intact uterus are coadministered a progestin to reduce the incidence of endometrial cancer. Also, a personal or familial history of cardiovascular disease or estrogen-dependent breast or endometrial cancer usually leads to exclusion from estrogen treatment. The use of estrogen in postmenopausal women has drastically declined following problems observed in studies from the Women’s Health Initiative and Heart and Estrogen Replacement Study (see Chapter 40). Other studies have shown that low doses of conjugated estrogens and micronized estradiol are effective in maintaining bone mineral density. However, as a result of controversies related to estrogen supplementation, other agents are being used to delay bone loss and reduce vasomotor symptoms. Although SERMs such as raloxifene do not significantly reduce vasomotor symptoms, they do have estrogenic effects on bone and have been approved for prevention and treatment of osteoporosis. SERMs are partial antagonists of estrogen on the mammary gland and uterus, possibly because of differential interactions with tissue-specific stimulatory and inhibitory cofactors (see Chapter 40).


Bisphosphonates are pyrophosphate analogs that have a bisphosphonate backbone. They strongly interact with hydroxyapatite crystals in bone and are specifically released at sites of bone resorption. The first generation of bisphosphonates included etidronate, which at high doses effectively inhibited osteoclast activity, decreased bone resorption, and reduced the incidence of fractures compared with untreated controls. However, there was no associated new bone growth. The second-generation bisphosphonates act like the first generation to inhibit osteoclasts, but they do not antagonize the effects of osteoblasts on bone rebuilding. Bisphosphonates are used to treat hypercalcemia, osteoporosis, and Paget’s disease of bone. There are several mechanisms involved, including activation of osteoclast apoptosis, antagonism of synthesis of isoprenyl groups through inhibition of the mevalonate pathway, and inhibition of activation of proteins required for osteoclast activity.

Other Agents Affecting Calcium Metabolism and Bone Formation

Sodium sulfate and the chelator ethylenediamine tetraacetic acid (EDTA) form complexes with Ca++ and accelerate its elimination. Hypercalcemia can also be normalized by the use of the loop diuretics furosemide and ethacrynic acid, which increase Ca++ excretion concomitantly with Na+ excretion, and the glucocorticoids, which decrease Ca++ absorption and increase excretion. It is important to note that the benzothiadiazide diuretics are contraindicated, because they decrease Ca++ excretion and can increase the risk of hypercalcemia. The antitumor agent plicamycin inhibits bone resorption and is administered by injection to treat testicular tumors and the hypercalcemia associated with malignancies. Because of its side effects, it is not used for other conditions.

Although fluoride is still used outside of the United States because of its documented effects to stimulate bone formation, the bones formed appear weaker than normal, leading to an increased incidence of fractures. The lack of confidence in the structural integrity of the new bone formed has led to decreased enthusiasm for the use of fluoride.

The mechanisms of action of compounds affecting Ca++ and bone metabolism are summarized in Table 44-1.

TABLE 44–1 Mechanisms of Action of Agents Altering Bone and Ca++ Metabolism



Increase intestinal Ca++ absorption

Vitamin D metabolites

PTH (indirect)

Increase renal Ca++ excretion

Na+ sulfate, EDTA*

Loop diuretics


Increase bone reabsorption


Vitamin D metabolites

Increase bone formation

Teriparatide (intermittent injection to achieve low PTH levels)

Second-generation bisphosphonates

Decrease intestinal Ca++ absorption


Calcitonin (postprandial)

Decrease renal Ca++ excretion


Decrease bone resorption





* Agent is less commonly used because of high risk-to-benefit ratio compared with other available drugs.


Vitamin D

Vitamin D, 25-hydroxyvitamin D (calcifediol), and 1,25-dihydroxyvitamin D (calcitriol) are absorbed rapidly after oral administration (Table 44-2). Bile salts are required, however, and absorption is impaired in patients with biliary cirrhosis. Absorption is also decreased during steatorrhea or an excessive loss of fat in the feces. Vitamin D compounds circulate bound to a specific vitamin D-binding protein, a slightly acidic monomeric glycoprotein synthesized in liver, and are metabolized to inactive glucuronides. It has been proposed that 24,25-dihydroxyvitamin D may have unique mineralization properties, although this is not well established. Clearly, 1,24,25-trihydroxyvitamin D is less active than its precursor, 1,25-dihydroxyvitamin D. Vitamin D is stored for long periods in liver, fat, and muscle.

TABLE 44–2 Pharmacokinetic Parameters



Teriparatide is administered by daily subcutaneous injections (20 μg). It is mandatory to achieve low circulating levels to promote new bone, because higher levels lead to resorption. Peak plasma concentrations are attained rapidly in normal individuals and are cleared with a mean half-life of 75 minutes. Because new bone is lost after cessation of teriparatide administration, termination of treatment is followed by administration of an antiresorptive agent such as a bisphosphonate or calcitonin.


Calcitonin is weakly bound to plasma proteins, has a short plasma half-life, and is metabolized rapidly by both liver and kidney.

Estrogens and Selective Estrogen Receptor Modulators

The estrogens used for prevention of osteoporosis include conjugated estrogens and micronized estrogen. Their pharmacokinetics and those of the SERMs are discussed in Chapter 40.


The bisphosphonates are available orally for use at weekly or monthly intervals and by injection quarterly or once per year. Because of poor oral absorption (1% to 6%), the bisphosphonates must be taken in the morning on an empty stomach with no food or other medication. In addition, individuals must remain in a standing or sitting position for at least 30 minutes. Bisphosphonates are not significantly metabolized, and after oral administration, approximately half the drug is excreted by the kidneys within 72 hours. The remainder of the absorbed drug is bound to hydroxyapatite in bone and can remain bound for years until resorption occurs at the sites where it is bound.

Relationship of Mechanisms of Action to Clinical Response

Vitamin D and Metabolites

Vitamin D and its active metabolites are used primarily for the treatment of rickets, osteomalacia, and hypocalcemia. The actions of vitamin D compounds to increase Ca++ absorption form the basis for their antirachitic activity. Their effects on Ca++ release from bone likely contribute to their hypercalcemic effect. Use of calcifediol and calcitriol is logical if a defect in the formation of these metabolites is present. Alternatively, larger doses of the precursor can be given to produce sufficient concentrations of active metabolites to increase serum Ca++. Therefore doses of vitamin D more than 10 times greater than those used for simple replacement therapy are used to treat hypoparathyroidism or vitamin D-resistant rickets. Calcipotriol, applied topically, can promote keratinocyte differentiation without affecting Ca++ metabolism and is used for the treatment of psoriasis. 19-Nor-1α,25-dihydroxyvitamin D2 can suppress the parathyroid glands with minimal hypercalcemic effects and is used to inhibit PTH secretion for the treatment of renal osteodystrophy, where impaired renal function and hydroxylation of vitamin D result in secondary hyperparathyroidism.


Teriparatide is approved for use in women who have a history of severe osteoporosis, multiple risk factors for fracture, or a history of osteoporotic fractures, or who are intolerant to previous osteoporosis therapy. It is also approved for use for hypogonadal osteoporosis in men. If administered properly once daily, teriparatide has an anabolic effect on bone and facilitates increased bone density and reduced incidence of fractures.


Calcitonin inhibits osteoclast activity and thus is an antiresorptive agent. It is used for the treatment of Paget’s disease of bone to inhibit abnormal bone turnover. It is also used to treat osteoporosis; however, it is less effective than estrogen or the bisphosphonates. Although used in treatment of hypercalcemia of malignancy, its effects in this setting are somewhat delayed and less dramatic than those of other agents.

Estrogens and Selective Estrogen Receptor Modulators

Estrogens and SERMs inhibit osteoclast activity by inhibiting the expression of local inflammatory interleukins and other cytokines and produce inhibition of bone resorption and increased bone density. Estrogen treatment started at the time of menopause prevents bone loss and decreases fractures. These compounds are used for both the prevention and treatment of osteoporosis.


Bisphosphonates are highly effective inhibitors of osteoclast activity and are used in the treatment of osteoporosis, Paget’s disease of bone, and hypercalcemia.

Pharmacovigilance: Clinical Problems, Side Effects, and Toxicity

The clinical problems associated with the use of compounds that alter Ca++ metabolism and bone formation are summarized in the Clinical Problems Box.

Vitamin D and Calcium Salts

Excess vitamin D and its metabolites can lead to hypercalcemia. The adverse effects of hypercalcemia are dose dependent and include abdominal pain, constipation, and nausea, increased risk of kidney stones, and soft tissue calcification. The immediate risk is greatest for 1,25-dihydroxyvitamin D, because this metabolite bypasses the enzyme that is feedback regulated, the renal 1α-hydroxylase. However, because 1,25-dihydroxyvitamin D has the shortest half-life, hypercalcemia and the risk of cumulative effects are potentially less than for the other metabolites. There is an increased risk of toxicity in patients with impaired renal function. Patients receiving vitamin D alone or with Ca++ must have serum Ca++ concentrations monitored, and treatment must be discontinued as Ca++ levels are restored or if hypercalcemia occurs. Benzothiadiazide diuretics, which decrease Ca++ excretion, can increase the risk of hypercalcemia from vitamin D. Drug interactions can occur with phenobarbital, phenytoin, and glucocorticoids, all of which interfere with vitamin D activation, as well as actions of metabolites on target tissues.


Hypercalcemia is a potential side effect of this PTH analog, because bone resorption can be stimulated if levels become elevated beyond those to produce the anabolic effect. This risk is lessened if the drug is administered intermittently, as in therapy of osteoporosis. Adverse effects include nausea, headache, dizziness, and cramps; the safety of long-term use is unknown.


Local hypersensitivity reactions including rashes, other allergic reactions, and nausea have been noted in patients receiving calcitonin. Although calcitonin could elicit hypocalcemia, this is not common. A potential problem with calcitonin is a loss of effectiveness with prolonged use.


The major side effects are GI problems including heartburn, abdominal pain, gastroesophageal reflux disease, diarrhea, and esophageal irritation and ulceration. All these effects can be minimized with bisphosphonates approved and available for parenteral administration.


Vitamin D and Metabolites

Hypercalcemia (benzothiadiazides can increase risk of hypercalcemia)

Parathyroid Hormone

Hypercalcemia (uncommon with intermittent dosing)


Local hypersensitivity, loss of effectiveness


Gastrointestinal side effects, osteomalacia, bone pain

Etidronate decreases bone mineralization and has been reported to cause osteomalacia and bone pain.

New Horizons

Significant advances have been made in the management of severe hypercalcemia and diseases of the bone. Patients with severe hypercalcemia have serious pathological problems, which can be exacerbated by the inordinately high levels of Ca++ in the blood. Recent studies are convincing that the use of intravenous bisphosphonates offers a rapid reduction of Ca++, which is relatively safer than other agents that have been used. In addition, the availability and approval of bisphosphonates administered parenterally on a quarterly or yearly basis have increased compliance in individuals by decreasing the side effects of these agents. This has led to the reduced use of agents that have poor risk-to-benefit ratios including plicamycin, intravenous PO4−3 infusion, and chelating agents such as EDTA.

A new class of drugs, the calcimimetics (cinacalcet), have been shown to increase the sensitivity of the parathyroid gland to circulating levels of Ca++, which reduces PTH secretion and ultimately blood Ca++ levels. In clinical trials cinacalcet had rapid bioavailability, which increased its ability to promptly reduce PTH in a concentration-dependent manner. Over a 2-year study this drug normalized serum Ca++ without altering bone mineral density. Cinacacet has been approved for the treatment of secondary hyperparathyroidism caused by chronic renal disease, and PTH-secreting parathyroid carcinoma. The principal adverse event from chronic use is hypocalcemia requiring frequent monitoring of Ca++ and titration of dosage to minimize this effect.

For the treatment of bone diseases associated with increased resorption, the second-generation bisphosphonates appear to offer modest improvement in bone mineral density. However, the teriparatide is even more effective and offers greater increases in lumbar spine at a more rapid rate. As these agents are used earlier in the disease process before significant bone loss, results are likely to improve.


Vitamin D, Metabolites, and Analogs

Calcifediol (Calderol)

Calcipotriene (Dovonex)

Calcitriol (Rocaltrol)

Dihydrotachysterol (DHT, Hytakerol)

Doxercalciferol (Hectorol)

Ergocalciferol (Calciferol, Drisdol)

Paricalcitol (Zemplar)


Alendronate (Fosamax)

Etidronate (Didronel)

Ibandronate (Boniva)

Pamidronate (Aredia)

Risedronate (Actonel)

Tiludronate (Skelid)

Zoledronic acid (Zometa, Reclast)

Calcitonin (Calcimar, Cibacalcin, Miacalcin)

Cinacalcet (Sensipar)

Teriparatide-injection (Forteo)

Raloxifene (Evista)


Anonymous. A once-yearly IV bisphosphonate for osteoporosis. Med Lett Drugs Ther. 2007;49:89-90.

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Anonymous. Teriparatide (forteo) for osteoporosis Treat Guidel Med Lett 2008; 6:67-74. Med Lett Drugs Ther. 2003;45:9-11.

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Khosla S, Melton LJ. Osteopenia. N Engl J Med. 2007;356:2293-2300.

Rosen CJ. Postmenopausal osteoporosis. N Engl J Med. 2005;353:595-603.

Seeman E, Delmas PD. Bone quality-the material and structural basis of bone strength and fragility. N Engl J Med. 2006;354:2250-2261.


1. Which of the following agents is a partial estrogen receptor agonist that is used to reduce bone loss associated with postmenopausal osteoporosis?

A. Calcitonin

B. Clomiphene

C. Medroxyprogesterone acetate

D. Raloxifene

E. Tamoxifen

2. Which of the following agents that can be used to treat osteoporosis will promote bone deposition at low intermittent levels and bone resorption at higher chronic dosages?

A. Calcitonin

B. Calcitriol

C. Calcium salts

D. Teriparatide

E. Second-generation bisphosphonates

3. Which of the following agents that can be used to treat osteoporosis can act to increase bone density by antagonizing the action of osteoclasts and are not inhibitory to the action of osteoblasts?

A. Calcium salts and DHT

B. Estrogen analogs

C. Inorganic phosphate (Pi)

D. Raloxifene

E. Second-generation bisphosphonates

4. Which of the following pathophysiological situations will contribute to the hypercalcemia associated with primary hyperparathyroidism?

A. Decreased production of calcitonin leading to loss of its antagonizing effects on bone resorption

B. Decreased renal excretion of Ca++

C. Decreased urinary loss of PO4−3, which promotes the formation of calcitriol

D. Increased hepatic formation of 25-hydroxyvitamin D, which promotes increased bone resorption

E. Increased movement of intracellular Ca++ from soft tissues to the blood