AHFS Class:

• Antiparathyroid Agents 68:24.04

Generic Name(s):

• Calcitonin (Salmon)

Calcitonin, a polypeptide hormone secreted by the parafollicular cells (C cells) of the thyroid gland in mammals and by the ultimobranchial gland in birds and fish, acts predominantly on bone to lower serum calcium concentration and inhibit bone resorption.

Calcitonin salmon is prepared synthetically and contains the 32 amino acids in the same linear sequence as occurs in natural calcitonin of salmon origin.125,127 Calcitonin salmon also is prepared using recombinant DNA technology; calcitonin salmon prepared by recombinant DNA technology is structurally identical to calcitonin salmon produced by chemical synthesis.145

Paget Disease

Calcitonin salmon is used parenterally for the management of Paget disease of bone (osteitis deformans). In most patients with Paget disease, only small areas of bone are involved and patients are usually asymptomatic; mild symptoms in these patients usually can be controlled with analgesics. Treatment with calcitonin or a bisphosphonate (e.g., alendronate, etidronate, pamidronate, risedronate) should be considered in patients with biochemical markers suggestive of an increase in bone remodeling, those who are symptomatic, and those at risk for future complications from their disease (e.g., those with pagetic lesions in weight-bearing regions or adjacent to joints).143

The effectiveness of calcitonin has been demonstrated in patients with moderate to severe disease characterized by multiple bone involvement (polyostotic) and elevated concentrations of serum alkaline phosphatase and urinary hydroxyproline. Serum alkaline phosphatase and urinary hydroxyproline concentrations have decreased and bone pain has been relieved in most patients studied. Symptomatic relief of bone pain is usually evident within 2-8 weeks after initiating therapy.100,102,118 A reversal of neurologic deficits and diminished hearing loss has occurred in a few patients. A small number of patients with increased cardiac output secondary to extensive Paget disease of bone have had measurable decreases in cardiac output while receiving calcitonin (possibly secondary to decreased blood flow in bone during calcitonin therapy);99,100,101,102,118,119,125 however, in a few similar patients, no appreciable changes in cardiac output were observed.20 In some patients, calcitonin has produced radiologic regression of pagetic lesions. Bone biopsies have demonstrated that normal new bone formation has occurred following administration of the hormone.

Patients treated chronically with calcitonin frequently show steady improvement (clinically and biochemically) with a plateau after 6-9 months of therapy and clinical improvement may continue despite diminution or no further improvement in biochemical parameters; further reductions in biochemical parameters are unusual. Some investigators believe that this plateau may result from a direct escape of the bone cells from the inhibitory effects of calcitonin. Although antibodies to calcitonin salmon have been reported in 30-50% of patients treated for 2-18 months with the drug, the plateau in biochemical response to the hormone does not appear to correlate with the development of antibodies, and clinical response often continues despite the presence of antibodies.22,33,99,100,101,102,105,108,109,110,111,112,115,125 Occasionally, antibody-induced resistance to calcitonin salmon may develop and generally is characterized by high antibody titers, biochemical relapse, unresponsiveness to the acute hypocalcemic effect of the hormone, and responsiveness to calcitonin of another origin (e.g., human).22,33,99,100,101,102,105,108,109,110,111,112,115,125 Patient compliance should always be confirmed whenever relapse occurs. Once relapse occurs, increased calcitonin salmon dosage rarely exerts further favorable influence on symptoms of Paget disease of bone. Following discontinuance of calcitonin, biochemical parameters return to pretreatment values over several months, although clinical response may persist for a year or longer.98,100,104,109,123,124

Hypercalcemia

Calcitonin salmon is used parenterally for the early treatment of hypercalcemic emergencies, along with other appropriate agents, when a rapid decrease in serum calcium concentration is required, until more specific treatment of the underlying disease can be accomplished. The drug may also be added to existing therapeutic regimens for the treatment of hypercalcemia, such as IV fluids and furosemide, oral phosphate or corticosteroids, or other agents. Calcitonin has been shown to decrease serum calcium in hypercalcemic patients with carcinoma (with or without demonstrated metastases), multiple myeloma, or primary hyperparathyroidism; patients with primary hyperparathyroidism have a lesser response.

Postmenopausal Osteoporosis

Calcitonin salmon is used parenterally or intranasally for the treatment of osteoporosis in women who are 5 or more years postmenopausal.125,127,136,145

In addition to adequate intake of calcium/vitamin D and other lifestyle modifications (e.g., exercise, avoidance of excessive alcohol and tobacco use), experts recommend that pharmacologic therapy for osteoporosis be considered in postmenopausal women who are at high risk of fractures (generally those who have experienced a previous hip or vertebral fracture or who have low bone mineral density [BMD]);147,148 pharmacologic therapy also may be considered in postmenopausal women who have low bone mass, although there is less evidence supporting overall fracture risk reduction in such patients.147 When selecting an appropriate pharmacologic agent, use of a drug with proven antifracture efficacy is recommended.148 Experts recommend calcitonin as one of several drugs that may be used, generally as a last-line therapy.147,148 Choice of therapy should be individualized based on the potential benefits (with regard to fracture risk reduction) and adverse effects of therapy as well as patient preferences, comorbidities, and risk factors.147,148

Efficacy of calcitonin salmon nasal spray has been evaluated in placebo-controlled and active-controlled studies.127,138,139,140,141,145 In a double-blind, placebo-controlled, dose-response study in women with BMD values at least 2 standard deviations below premenopausal mean values, therapy with 200 units of calcitonin salmon administered intranasally once daily for 2 years was associated with increased BMD in the lumbar spine.127,138,139,145 In a comparative study in postmenopausal women with osteoporosis (defined as lumbar spine or femoral neck BMD values at least 2 standard deviations below premenopausal mean values) given either alendronate 10 mg daily or intranasal calcitonin salmon 200 units daily for 1 year, increases in BMD were greater with alendronate than with calcitonin at the lumbar spine (5.16 versus 1.18%), trochanter (4.73 versus 0.47%), and femoral neck (2.78 versus 0.58%).140 In a randomized study in postmenopausal women with osteoporosis, the risk of new vertebral fracture was reduced by 33% in those receiving intranasal calcitonin salmon 200 units daily compared with those receiving placebo;141 however, the validity of these results has been questioned because of the high (59%) study dropout rate and the unexpected finding that calcitonin salmon given at a dosage of 400 units daily was not associated with a reduction in fracture occurrence.141,144 Further study is needed to fully establish the effect of calcitonin salmon nasal spray on fracture rate in postmenopausal women with osteoporosis.144

Efficacy of calcitonin salmon administered parenterally is based on increases in total body calcium.122,125 The effect of parenteral calcitonin salmon on fracture rates remains to be fully evaluated.122,125

When calcitonin is used for the treatment of postmenopausal osteoporosis, the effect of the drug can be monitored by periodic measurements of BMD.125,127,145 The effect of intranasal calcitonin on biochemical markers of bone turnover has not been consistent in postmenopausal women; evaluation of clinical response to intranasal calcitonin should not rely on biochemical markers of bone turnover alone.127,145

Glucocorticoid-induced Osteoporosis

Calcitonin salmon has been used parenterally and intranasally for the treatment of glucocorticoid-induced osteoporosis†; however, other therapies generally are preferred.126,622 Calcitonin has been shown to increase BMD at the lumbar spine but not the femoral neck in patients receiving chronic glucocorticoid therapy; however, calcitonin does not appear to reduce the risk of radiographic vertebral fractures.126

The American College of Rheumatology (ACR) recommends optimizing calcium and vitamin D intake and lifestyle modifications (e.g., diet, smoking cessation, weight-bearing or resistance-training exercise) in all patients receiving long-term glucocorticoid therapy; in addition, pharmacologic therapy with an oral bisphosphonate is recommended in patients who are considered to be at moderate-to-high risk of fracture.622 Oral bisphosphonates generally are preferred because of their demonstrated antifracture benefits, safety, and cost.622

Other Uses

Calcitonin salmon has been used in the management of osteogenesis imperfecta†, and a limited number of patients have shown biochemical and/or symptomatic improvement.

Administration

Calcitonin salmon is administered by subcutaneous or IM injection. 125 Calcitonin salmon also is administered intranasally as a nasal spray.127,145

Skin testing prior to initiation of therapy should be considered for patients with suspected sensitivity to calcitonin salmon.125,127,145 A skin test protocol is available from the Medical Services Department of Novartis Pharmaceutical Corporation or Upsher-Smith Laboratories.125,127,145

Parenteral Administration

Calcitonin salmon may be administered by subcutaneous or IM injection.125 When the volume of calcitonin salmon injection to be administered exceeds 2 mL, IM injection is preferable and multiple sites of injection should be used.125

The subcutaneous route of administration is preferred for patient self-administration.125 Patients and/or other individuals who may be administering calcitonin salmon should be carefully instructed about proper administration techniques, including aseptic technique.125 Because treatment with calcitonin is usually prolonged, it is desirable to alternate injection sites.

Intranasal Administration

Calcitonin salmon is administered by nasal inhalation using a metered-dose nasal spray pump.127,145 Patients should be instructed carefully on use of the pump and given a copy of the patient instructions provided by the manufacturer.127,145

Prior to initial use, the nasal spray pump must be primed; it is not necessary to prime the pump before each daily dose.127,145 The nasal solution should be at room temperature before the pump is primed and the initial dose administered.127,145 To prime the pump, the bottle is held upright and the 2 white side arms of the pump depressed toward the bottle until a full spray is produced.127 The manufacturer of Fortical^® states that the side arms need to be depressed at least 5 times until a full spray is produced.145 Calcitonin salmon is administered daily as a single spray into one nostril; patients should be instructed to alternate nostrils daily.127,145 Patients should hold their head upright, insert the nozzle into one nostril, and then firmly depress the pump toward the bottle.127,145

Dosage

Dosage of calcitonin salmon is expressed in terms of International Units (units).125,127,145

Paget Disease

Parenteral Dosage

The usual initial adult dosage of calcitonin salmon for the management of Paget disease of bone is 100 units daily given by subcutaneous or IM injection. The effect of the drug should be monitored by periodic determinations of serum alkaline phosphatase and urinary hydroxyproline excretion as well as evaluation of symptoms. If clinical and/or biochemical improvement occurs, it is usually evident within the first few months of therapy. When clinical or biochemical improvement occurs, the patient can often be maintained on a dosage of 50 units daily or every other day; however, 100 units daily should be continued in patients with a serious deformity or neurologic involvement.125 Benefits of long-term calcitonin therapy generally persist for weeks or months after withdrawal of the drug, usually followed by return to pretreatment status. When patients who show a good initial response to calcitonin salmon relapse while on continued therapy, a dosage increase beyond 100 units daily does not usually produce an improved response.98,101,105,109,110,111,112

Hypercalcemia

Parenteral Dosage

For the management of hypercalcemia, the recommended initial adult dosage of calcitonin salmon is 4 units/kg every 12 hours given by subcutaneous or IM injection. If the response to this dosage is not satisfactory after 1 or 2 days, dosage may be increased to 8 units/kg every 12 hours. If the response remains unsatisfactory after 2 more days, dosage may be increased to a maximum of 8 units/kg every 6 hours.

Calcitonin salmon has also been administered in a dosage of 2-16 units/kg by IV infusion† every 12 hours in the management of hypercalcemia.

Postmenopausal Osteoporosis

Intranasal Dosage

The commercially available calcitonin salmon metered-dose pumps deliver 0.09 mL of solution containing 200 units of drug per actuation.127,145 The pumps deliver about 30 metered doses.127,145 For the treatment of postmenopausal osteoporosis, the recommended dosage of calcitonin salmon is 200 units (one actuation) daily in conjunction with adequate calcium and vitamin D intake.127,145 The spray pump should be discarded after 30 actuations have been used since the correct drug dose per actuation cannot be assured if used for additional doses.127

Parenteral Dosage

The minimum effective dosage of calcitonin salmon for the treatment of postmenopausal osteoporosis has not been established.125 Results from one placebo-controlled study indicate that administration of 100 units every other day in conjunction with adequate calcium and vitamin D intake may be effective in preserving vertebral bone mineral density (BMD).125

Other Uses

For the treatment of osteogenesis imperfecta†, calcitonin salmon has been administered parenterally in a dosage of 2 units/kg 3 times weekly combined with daily oral calcium supplementation.120

Adverse effects associated with the clinical use of calcitonin salmon usually have been infrequent and mild, although adverse effects may occasionally be severe enough to require discontinuance of the drug.

The frequency of common adverse effects reported in patients receiving parenteral calcitonin salmon is higher than that reported in patients receiving calcitonin salmon nasal spray.127,145

GI Effects

Adverse effects of parenteral calcitonin salmon most frequently involve the GI tract. Transient nausea, with or without vomiting, is the most common adverse effect of parenteral calcitonin salmon, occurring in 10% of patients receiving the drug. Nausea usually is mild and diminishes or disappears with continued therapy. Nausea and vomiting may occur within 30 minutes after injection of calcitonin118 and may be minimized by administering the drug at bedtime.100,102,118 Nausea, with or without vomiting, has been reported in 1.8% of patients receiving calcitonin salmon nasal spray.127,145

Other adverse GI effects of calcitonin include anorexia/poor appetite, diarrhea, epigastric discomfort, and abdominal pain. An unusual (e.g., salty, metallic) taste sensation has also been reported in patients receiving parenteral calcitonin salmon.125

Dermatologic, Sensitivity, and Immunologic Reactions

Flushing of the face, ears, hands, and feet may occur within minutes after injection of calcitonin salmon, but usually is well tolerated.24,100,102,104,106,107,117,118,120,125 Flushing may be minimized by administering the drug at bedtime.22,100,102 Flushing has been reported in 2-5% of patients receiving parenteral calcitonin and in less than 1% of those receiving intranasal calcitonin.125,127,145

Tenderness22 and/or tingling117 of the palms and soles have also been reported in patients receiving parenteral calcitonin. A local inflammatory reaction may occur at the site of subcutaneous or IM injection of calcitonin salmon.118,125 Rashes, including a maculopapular eruption, erythema, and urticaria, have been reported occasionally in patients receiving calcitonin.

Serious hypersensitivity reactions, including bronchospasm, swelling of the tongue or throat, and anaphylactic shock, have occurred in a few patients receiving parenteral calcitonin salmon; at least one death attributed to anaphylaxis has been reported with this drug.125 Allergic-type reactions also have occurred in patients receiving intranasal calcitonin.127,145

Circulating antibodies to calcitonin salmon may occur in 30-50% of patients after 2-18 months of treatment with parenteral calcitonin.22,33,100,101,102,105,108,109,110,111,112,115 The concentrations of antibodies are not usually clinically important; however, a few patients have shown very high calcitonin antibody titers. Patients with Paget disease of bone who are receiving calcitonin salmon often resemble treated diabetic patients in whom low titers of insulin-binding antibodies frequently develop but who rarely manifest clinical resistance to insulin.22,102,105 When a patient who has shown a good initial response to calcitonin salmon relapses, the possibility of substantial antibody formation should be investigated.100,102,105,110,111 Critical clinical evaluation may be employed or calcitonin salmon antibody titers may be determined using an appropriate specialized test.100,105,111

Nasal Effects

Alterations of the nasal mucosa or transient nasal conditions occur frequently in patients receiving calcitonin salmon nasal spray.127,138,140,141,145 Adverse nasal effects were described as mild, moderate, or severe in 70, 25, or 5% of those reporting nasal symptoms.127,145 Rhinitis, epistaxis, or sinusitis has been reported in 12, 3.5, or 2.3%, respectively, of patients receiving intranasal calcitonin for the treatment of postmenopausal osteoporosis.127,145 A small nasal wound occurred in at least one patient receiving calcitonin salmon 400 units daily.127,145 Smoking does not appear to contribute to the occurrence of adverse nasal effects.127,145

Other Adverse Effects

During the first few days of parenteral calcitonin administration, some patients have experienced diuresis and increased urinary sodium excretion which returned to baseline levels after 5-7 days of continued therapy.21 Urinary frequency100,102,104,107,111 and nocturia125 also have been reported.

Pruritus of the earlobes, sensation of fever, eye pain, and edema of the feet have been reported following parenteral administration of calcitonin salmon.125 Headache, back pain, and arthralgia have occurred in patients receiving intranasal calcitonin.127,145

Precautions and Contraindications

Because calcitonin salmon is protein in nature, the possibility of a systemic allergic reaction should be considered, and appropriate measures for treatment of a hypersensitivity reaction should be readily available.8,125,127,145 Serious, potentially fatal hypersensitivity reactions have been reported in patients receiving parenteral calcitonin salmon.125 Hypersensitivity reactions should be differentiated from generalized flushing and hypotension associated with administration of the drug.125,127,145 Skin testing should be considered prior to initiating therapy with calcitonin salmon in patients with suspected sensitivity to this calcitonin.8,125,127,145

Nasal examination with visualization of the nasal mucosa, turbinates, septum, and mucosal blood vessel status is recommended prior to initiation of therapy with calcitonin salmon nasal spray, periodically during therapy, and any time nasal symptoms occur.127,145 If severe ulceration of the nasal mucosa (e.g., ulcers exceeding 1.5 mm in diameter or penetrating below the mucosa, ulcers associated with heavy bleeding) occurs, discontinuance of calcitonin salmon nasal spray is recommended.127,145 While smaller ulcers frequently heal despite continued calcitonin therapy, treatment with the nasal spray should be temporarily interrupted until healing has occurred.127,145

The possibility of hypocalcemic tetany following parenteral administration of calcitonin should be considered8,99,111,125 and calcium injection should be readily available, particularly during administration of the first several doses of parenteral calcitonin salmon.125

Patients receiving chronic therapy with parenteral calcitonin salmon should have periodic examinations of urine sediment because coarse granular casts and casts containing renal tubular epithelial cells were reported in some young adult volunteers at bedrest who received calcitonin salmon in a study of its effect on immobilization osteoporosis.34,125 Creatinine clearance was not altered, proteinuria did not occur, and urine sediment returned to normal within 4 days when the drug was discontinued.34 No other investigators have reported this adverse reaction to date.125

Radiographic evidence of marked progression of pagetic lesions, possibly with some loss of definition of periosteal margins, must be evaluated carefully to rule out the possibility of osteogenic sarcoma since the frequency of this tumor is increased in Paget disease of bone.125

Calcitonin salmon is contraindicated in patients with hypersensitivity to this calcitonin.125,127,145

Pediatric Precautions

Calcitonin salmon has been used rarely in children with juvenile Paget disease, but the relationship of these pediatric bone disorders to Paget disease in adults has not been established.125 Calcitonin salmon also has been used rarely in children with idiopathic juvenile osteoporosis, but the relationship between bone disorders in children and postmenopausal osteoporosis has not been established.127,145 Currently, there are inadequate safety and efficacy data to support the use of calcitonin in children.125,127,145

Geriatric Precautions

When the total number of patients studied in clinical trials of calcitonin salmon nasal spray is considered, approximately 50% were 65-74 years of age while 20% were 75 years of age or older.127,145 The incidence of adverse nasal effects (i.e., rhinitis, irritation, congestion) was higher in geriatric adults, particularly in those older than 75 years of age, than in younger adults.127,145 Most adverse nasal effects were described as mild.127,145 Although no overall difference in response was observed between geriatric adults and younger adults in other clinical reports, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.127,145

Mutagenicity and Carcinogenicity

An increased incidence of pituitary adenomas has been observed in rats given calcitonin salmon subcutaneously in dosages of 80 units/kg daily (16-19 times the recommended human parenteral dose and 130-160 times the human intranasal dose based on body surface area).125,127,145 Calcitonin salmon has not exhibited mutagenic activity to date in microbial and mammalian test systems.125,127,145

Pregnancy and Lactation

Pregnancy

Calcitonin salmon has been shown to decrease fetal birthweight in rabbits when given in dosages 14-56 times the recommended human parenteral dose.125 Because calcitonin does not cross the placenta, this adverse fetal effect may result from metabolic effects of calcitonin in the pregnant animal.125 127,145 Parenteral calcitonin salmon should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.125 Calcitonin salmon nasal spray should not be used in pregnant women.127,145

Lactation

Calcitonin inhibits lactation in animals.125,127,145 It is not known whether calcitonin salmon is distributed into milk,125,127,145 although drug distributed into milk and ingested by the infant is likely to be inactivated in the GI tract and therefore unlikely to be absorbed by the nursing infant.98 Because studies to determine GI absorption of calcitonin in nursing infants have not been performed to date, use of calcitonin salmon in nursing women is not recommended.125,127,145

Formal drug interaction studies have not been performed to date.125,127,145

Prior use of bisphosphonates in patients with Paget disease appears to reduce the antiresorptive response to intranasal calcitonin salmon in these patients.127,145

Pharmacology

The pharmacologic activity of calcitonin salmon and calcitonins of mammalian origin is the same,98,99,100,101,102,103,104,109,125 but calcitonin salmon is substantially more potent on a weight basis and has a longer duration of action.100,103,109,112,114 Calcitonin acts predominantly on bone to lower serum calcium concentration, but also has direct effects on the kidneys and the GI tract.

The physiologic role of calcitonin is not completely known. Calcitonin is secreted in response to the concentration of calcium in the blood perfusing the thyroid gland. Thus, high serum calcium concentrations cause increased secretion of calcitonin which, in turn, inhibits bone resorption. Calcitonin may act as an emergency hormone lowering serum calcium in patients with acute hypercalcemia. It is believed that calcitonin through its action on bone plays a role, along with parathyroid hormone (PTH), in calcium homeostasis. GI hormones, particularly gastrin, can also stimulate calcitonin secretion and calcitonin may have a regulatory function in the release or catabolism of gastrin.

Calcitonin directly inhibits osteoclastic bone resorption, altering the function and/or number of osteoclasts. A single therapeutic dose of calcitonin produces a marked transient inhibition of bone resorption; however, prolonged administration of calcitonin usually produces a persistent but smaller decrease in the rate of bone resorption. Presumably, calcitonin interacts with a specific receptor site on the plasma membrane of the osteoclast which results in intracellular accumulation of cyclic adenosine monophosphate (AMP) and alters calcium and/or phosphate transport across the plasma membrane. It also appears that calcitonin inhibits osteocytic osteolysis. Calcitonin's inhibition of bone resorption decreases both mineral release and matrix or collagen breakdown. Calcitonin opposes the effects of osteoclast stimulators such as PTH; however, calcitonin does not act as a competitive inhibitor of PTH. During hypocalcemic responses to exogenous calcitonin, PTH concentrations show a transient rise, but investigators have not been able to demonstrate persistent hypersecretion of PTH in patients treated chronically with calcitonin. There is some evidence that osteoclasts may escape the inhibitory effects of calcitonin, and bone resorption resumes at its original rate despite the continued presence of the hormone. Calcitonin may promote bone accretion by increasing osteoblastic activity; however, calcitonin's effect on osteoblasts has not been conclusively established and there is some evidence that the hormone may have a suppressive effect on the function and number of osteoblasts.

In most patients with Paget disease of bone (osteitis deformans), calcitonin causes a decrease in the rate of bone turnover with a resultant decrease in elevated serum alkaline phosphatase concentrations and urinary hydroxyproline excretion. These biochemical changes appear to correspond to changes toward more normal bone formation. There is considerable interindividual variation, but bone turnover generally decreases by about 30-50% after about 6 months of parenteral calcitonin therapy, as determined by reductions in serum alkaline phosphatase and urinary hydroxyproline excretion, and generally remains at this level during continued therapy.22,98,100,101,102,105,106,107,109,111 The mechanism for this plateau in biochemical parameters is not known, but clinical response generally continues despite the plateau.22,100,102,105,108,109,110,111 Following discontinuance of calcitonin, these biochemical parameters return toward pretreatment values, although symptomatic response may persist.98,100,104,109,123,124 The extent to which calcitonin can inhibit bone resorption may depend on the existing rate of bone resorption—the higher the rate of bone resorption, the more evident the inhibition of bone resorption following calcitonin administration. In healthy adults who have a relatively low rate of bone resorption, exogenous calcitonin produces only a slight decrease in serum calcium but, in healthy children and in patients with generalized Paget disease, bone resorption is increased and serum calcium concentrations show a greater decrease in response to calcitonin administration.

Calcitonin can decrease serum calcium concentration in hypercalcemic patients with carcinoma (with or without demonstrated metastases), multiple myeloma, or primary hyperparathyroidism; patients with primary hyperparathyroidism have a lesser response. Serum calcium concentration tends to be reduced to a greater extent during calcitonin therapy in those patients with higher serum calcium concentrations. The decrease in serum calcium occurs about 2 hours after the first dose of parenteral calcitonin salmon and persists for about 6-8 hours; the average reduction of 8-hour post-injection serum calcium in clinical trials was about 9%. During clinical trials, parenteral administration of calcitonin salmon every 12 hours maintained a reducing effect on serum calcium for about 5-8 days, the time period evaluated for most patients.

Calcitonin promotes renal excretion of calcium, phosphate, sodium, magnesium, chloride, and potassium by decreasing tubular reabsorption of these ions. These effects have been observed in individuals receiving parenteral calcitonin; the effect of calcitonin salmon nasal spray on renal excretion and/or tubular absorption of these ions has not been evaluated.127,145 In some patients, a decrease rather than an increase in urinary calcium occurs following administration of parenteral calcitonin, because the inhibition of bone resorption has a greater impact on calcium excretion than the hormone's direct effect on tubular reabsorption. A transient increase in sodium and water excretion may occur following the first dose of calcitonin, but this diuretic effect usually is not observed with continued therapy, probably because of compensatory hypersecretion of aldosterone.

Calcitonin also acts on the GI tract causing an increase in jejunal secretion of water, sodium, potassium, and chloride, but not calcium. Short-term parenteral administration of calcitonin produces marked, transient decreases in the volume and acidity of gastric juice, and in the volume, trypsin content, and amylase content of pancreatic juice. It is not known if these effects continue during long-term parenteral calcitonin therapy. The effect of calcitonin salmon nasal spray on the GI tract has not been established.127,145

Pharmacokinetics

Absorption

Because of its polypeptide nature, calcitonin is destroyed in the GI tract and, therefore, must be administered parenterally or intranasally.

Following parenteral administration, calcitonin is absorbed directly into the circulation. The range of therapeutically effective plasma concentrations has not been established. Plasma concentrations of 0.1-0.4 ng/mL are achieved following subcutaneous administration of 200 units of calcitonin salmon. The onset of action of calcitonin salmon is immediate following IV administration and occurs in about 15 minutes following IM or subcutaneous administration. Calcitonin salmon has its maximum effect in about 4 hours following IM or subcutaneous administration. The duration of action of calcitonin salmon is 8-24 hours following IM or subcutaneous administration and 30 minutes to 12 hours following IV administration. Clinical and/or biochemical effects may not be evident in patients with Paget disease of bone until after several months of calcitonin therapy.

Calcitonin is rapidly absorbed from the nasal mucosa.127,145 Following intranasal administration of calcitonin salmon, peak plasma concentrations are attained within 31-39 minutes.127 Bioavailability of calcitonin salmon administered intranasally is approximately 3% (range: 0.3-30.6%) of that attained with IM administration of the drug.127,145 Accumulation of calcitonin was not observed in individuals receiving intranasal calcitonin salmon every 10 hours for up to 15 days.127,145

Distribution

It has not been determined whether calcitonin salmon enters CSF or is distributed into milk.125 Immunoreactive endogenous calcitonin, which was heterogeneous and included 2 forms larger than the monomer, has been detected in human milk in concentrations 10-40 times those in serum.113 Apparently, calcitonin does not cross the placenta.125,127,145

Elimination

Although the metabolism of calcitonin has not been extensively studied, it is believed that the hormone is rapidly metabolized, principally by the kidneys and in the blood and peripheral tissues. A metabolic clearance of 3.1 mL/kg per minute has been reported following IV infusion of calcitonin salmon in healthy individuals.114 The elimination half-life is about 43 minutes.127 Inactive metabolites, as yet unidentified, are excreted in urine. Little (0.1%) urinary excretion of unchanged calcitonin occurs.101,114,125

Chemistry and Stability

Chemistry

Calcitonin is a polypeptide hormone secreted by the parafollicular cells (C cells) of the thyroid gland in mammals and by the ultimobranchial gland in birds and fish. Calcitonin, from any source, is a 32-amino acid polypeptide chain with a disulfide bridge and a molecular weight of about 3600. Prolinamide at the carboxyl terminus, glycine at position 28, and 7 of the first 9 amino acids are common to all calcitonins, but the remaining amino acid sequence may differ considerably from that of human calcitonin, depending on the species.100,101,102,103,104 Structural relationships to potency and duration of effect are complex and may depend more on spatial relationships than on the amino acid sequence.100,101,103

Calcitonin is commercially available as calcitonin salmon.125,127 Calcitonin salmon and calcitonin human differ structurally at amino acids 2, 8, 11-13, 15-17, 19, 20, 22, 24, 26, 27, 29, and 31 in the sequence.98,99,100,125 The pharmacologic activity of these calcitonins is the same,98,99,100,101,102,103,104,109,125 but calcitonin salmon is substantially more potent on a weight basis (approximately 50 times that of calcitonin human) and has a longer duration of action.100,103,109,112,114

Calcitonin salmon is prepared synthetically and contains the 32 amino acids in the same linear sequence as occurs in natural calcitonin of salmon origin.125,127 Calcitonin salmon also is prepared using recombinant DNA technology; calcitonin salmon prepared by recombinant DNA technology is structurally identical to calcitonin salmon produced by chemical synthesis.145

Calcitonin salmon occurs as a white, fluffy powder and is very soluble in water and very slightly soluble in alcohol. The potency of calcitonin salmon is expressed in International Units (units) based on bioassay in comparison with the International Reference Preparation of Salmon Calcitonin for Bioassay, distributed by the National Institute for Biological Standards and Control, Holly Hill, London.

The commercially available calcitonin salmon injection contains sodium chloride, sodium acetate, and acetic acid; the injections also contain phenol as a preservative.125

Miacalcin^® nasal solution contains sodium chloride, hydrochloric acid, benzalkonium chloride, and purified water.127

Fortical^® nasal solution contains sodium chloride, citric acid, phenylethyl alcohol, benzyl alcohol, polysorbate 80, hydrochloric acid or sodium hydroxide (to adjust pH), and purified water.145

Stability

Calcitonin salmon injection should be refrigerated at 2-8°C.125

Miacalcin^® nasal solution should be stored at 2-8°C until the bottle is opened and the pump is primed for use.127 The bottle in use should be stored at 15-30°C in an upright position for up to 35 days.127 The nasal solution should be protected from freezing.127

Fortical^® nasal solution should be stored at 2-8°C until the bottle is opened and the pump is primed for use.145 The bottle in use should be stored at 20-25°C in an upright position for up to 30 days.145 The nasal solution should be protected from freezing.145

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

8. Mundy GR, Raisz LG. Calcitonin: background and uses. Drug Ther . 1975; 5:38-42.

20. Crosbie WA, Woodhouse NJY. Effect of salmon calcitonin treatment on bone turnover, cardiac output and oxygen transport in patients with Paget's disease. Clin Sci Mol Med . 1974; 48:5-6P.

21. Hamilton CR Jr. Effects of synthetic salmon calcitonin in patients with Paget's disease of bone. Am J Med . 1974; 56:315-22. [PubMed 4855941]

22. DeRose J, Singer FR, Avramides A et al. Response of Paget's disease to porcine and salmon calcitonins—effects on long-term treatment. Am J Med . 1974; 56:858-66. [PubMed 4857531]

24. Kanis JA, Horn DB, Scott RDM et al. Treatment of Paget's disease of bone with synthetic salmon calcitonin. Br Med J . 1974; 3:727-31. [PubMed 4472416]

33. Singer FR, Aldred JP, Neer RM et al. An evaluation of antibodies and clinical resistance to salmon calcitonin. J Clin Invest . 1972; 51:2331-8. [PubMed 4674133]

34. Hantman DA, Donaldson CL, Hulley SB. Abnormal urinary sediment during therapy with synthetic salmon calcitonin. J Clin Endocrinol Metab . 1971; 33:564-6. [PubMed 5106277]

98. Ciba Pharmaceutical Company. Cibacalcin^® (calcitonin human for injection) prescribing information. Summit, NJ; 1988 Feb.

99. Rorer. Calcimar^® (calcitonin salmon injection) prescribing information. Fort Washington, PA; 1989 Jun.

100. Hosking DJ. Paget's disease of bone: an update on management. Drugs . 1985; 30:156-73. [PubMed 3928323]

101. Austin LA, Heath HH III. Calcitonin: physiology and pathophysiology. N Engl J Med . 1981; 304:269-78. [PubMed 7003392]

102. Deftos LJ, First BP. Calcitonin as a drug. Ann Intern Med . 1981; 95:192-7. [PubMed 7258871]

103. Johl A, Rittel W. Chemistry of human calcitonin. In: Caniggia A, ed. Proceedings of the International Workshop on Human Calcitonin of Stresa. April 24, 1982:9-22.

104. MacIntyre I, Evans IMA, Hobitz HHG et al. Chemistry, physiology, and therapeutic applications of calcitonin. Arthritis Rheum . 1980; 23:1139-47. [PubMed 7191707]

105. Martin TJ. Treatment of Paget's disease with the calcitonins. Aust N Z J Med . 1979; 9:36-43. [PubMed 287441]

106. Evans RA. Treatment of Paget's disease of bone. Med J Aust . 1983; 1:159-62. [PubMed 6405139]

107. Grunstein HS, Clifton-Bligh P, Posen S. Paget's disease of bone: experiences with 100 patients treated with salmon calcitonin. Med J Aust . 1981; 2:278-80. [PubMed 7300759]

108. Avioli LV. Calcitonin therapy for bone disease and hypercalcemia. Arch Intern Med . 1982; 142:2076-9. [PubMed 7138154]

109. Hosking DJ. Paget's disease of bone. BMJ . 1981; 283:686-8. [PubMed 6793126]

110. Scuro LA, Lo Cascio V, Adami S. Therapeutic use of human calcitonin in patients with Paget's disease resistant to heterologous calcitonins. In: Caniggia A, ed. Proceedings of the International Workshop on Human Calcitonin of Stresa. April 24, 1982:181-91.

111. Singer FR, Fredericks RS, Minkin C. Salmon calcitonin therapy for Paget's disease of bone: the problem of acquired clinical resistance. Arthritis Rheum . 1980; 23:1148-54. [PubMed 7000081]

112. Rojanasathit S, Rosenberg E, Haddad JG Jr. Paget's bone disease: response to human calcitonin in patients resistant to salmon calcitonin. Lancet . 1974; 2:1412-5. [PubMed 4140329]

113. Bucht E, Arver S, Sjoberg HE et al. Heterogeneity of immunoreactive calcitonin in human milk. Acta Endocrinol . 1983; 103:572-6. [PubMed 6613498]

114. Huwyler R, Born W, Ohnhaus EE et al. Plasma kinetics and urinary excretion of exogenous human and salmon calcitonin in man. Am J Physiol . 1979; 236:E15-9. [PubMed 571211]

115. Dietrich FM, Macarol V, Dambacher MA et al. Immunology of synthetic human calcitonin. In: Caniggia A, ed. Proceedings of the International Workshop on Human Calcitonin of Stresa. April 24, 1982:57-67.

116. Dietrich FM, Fischer JA, Bijvoet OL. Formation of antibodies to synthetic human calcitonin during treatment of Paget's disease. Acta Endocrinol . 1979; 92:468-76. [PubMed 517048]

117. Gennari C, Passeri M, Chierichetti SM et al. Side-effects of synthetic salmon and human calcitonin. Lancet . 1983; 1:594-5. [PubMed 6131289]

118. Melick RA. Treatment of Paget's disease of bone. Med J Aust . 1985; 143:394-7. [PubMed 2932626]

119. Woodhouse NJY, Crosbie WA, Mohamedally SM. Cardiac output in Paget's disease: response to long-term salmon calcitonin therapy. Br Med J . 1975; 4:680. [PubMed 1203720]

120. Castells S, Colbert C, Chakrabarti C et al. Therapy of osteogenesis imperfecta with synthetic salmon calcitonin. J Pediatr . 1979; 95(5 Part 1):807-11. [PubMed 573785]

121. Jowsey J, Riggs BL, Kelly PJ et al. Calcium and salmon calcitonin in treatment of postmenopausal osteoporosis. J Clin Endocrinol Metab . 1978; 47:633-9. [PubMed 263316]

122. Gruber HE, Ivey JL, Baylink DJ et al. Long-term calcitonin therapy in postmenopausal osteoporosis. Metabolism . 1984; 33:295-303. [PubMed 6423929]

123. Avramides A, Flores A, DeRose J et al. Paget's disease of the bone: observations after cessation of long-term synthetic salmon calcitonin treatment. J Clin Endocrinol Metab . 1976; 42:459-63. [PubMed 1254686]

124. Evans IMA, Banks L, Doyle FH et al. Paget's disease of bone—the effect of stopping long-term human calcitonin and recommendations for future treatment. Metab Dis Relat Res . 1980; 2:87-92.

125. Novartis. Miacalcin^® (calcitonin-salmon) injection, synthetic prescribing information. East Hanover, NJ; 2002 Jul.

126. American College of Rheumatology Ad Hoc Committee on Glucocorticoid-induced Osteoporosis. Recommendations for the prevention and treatment of gluococorticoid-induced osteoporosis: 2001 update. Arthritis Rheum . 2001; 44:1496-503. [PubMed 11465699]

127. Novartis. Miacalcin^® (calcitonin-salmon) nasal spray prescribing information. East Hanover, NJ: 2006 Jun.

128. Wood AJJ. Treatment of postmenopausal osteoporosis. N Engl J Med . 1998; 338:736-46. [PubMed 9494151]

129. Committee on Educational Bulletins of the American College of Obstetricians and Gynecologists. ACOG Educational Bulletin: osteoporosis. Obstet Gynecol . 1998; 91:1-9. [PubMed 9464711]

130. Heaney RP. Bone mass, bone loss, and osteoporosis prophylaxis. Ann Intern Med . 1998; 128:313-4. [PubMed 9471936]

131. Seeman E. Osteoporosis: trials and tribulations. Am J Med . 1997; 103:74-89S. [PubMed 9236490]

132. European Foundation for Osteoporosis and Bone Disease, National Osteoporosis Foundation, and National Institute of Arthritis and Musculoskeletal and Skin Diseases. Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med . 1993; 94:646-50. [PubMed 8506892]

133. Osteoporosis Society of Canada Scientific Advisory Board. Clinical practice guidelines for diagnosis and management of osteoporosis. CMAJ . 1996; 155:1113-33. [PubMed 8873639]

134. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes of the Food and Nutrition Board, Institute of Medicine, National Academy of Sciences. Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D, and fluoride. Washington, DC: National Academy Press; 1997. Prepublication Copy.

135. Anon. Drugs for the prevention and treatment of postmenopausal osteoporosis. Treatment Guidelines from the Medical Letter . 2002;1:13-18.

136. National Osteoporosis Foundation. Physician's guide to prevention and treatment of osteoporosis. Apr 2003. From the National Osteoporosis Foundation web site ([Web]). Accessed 2005 Feb 14.

137. U.S. Preventive Services Task Force. Postmenopausal hormone replacement therapy for primary prevention of chronic conditions: recommendations and rationale. Ann Intern Med / 2002; 137-834-9.

138. Overgaard K, Hansen MA, Jensen SB et al. Effect of salcatonin given intranasally on bone mass and fracture rates in established osteoporosis: a dose-response study. BMJ . 1992; 305(6853):556-61. [PubMed 1393035]

139. Overgaard K, Lindsay R, Christiansen C. Patient responsiveness to calcitonin salmon nasal spray: a subanalysis of a 2-year study. Clin Ther . 1995 Jul-Aug; 17(4):680-5.

140. Downs RW Jr, Bell NH, Ettinger MP et al. Comparison of alendronate and intranasal calcitonin for treatment of osteoporosis in postmenopausal women. J Clin Endocrinol Metab . 2000; 85(5):1783-8. [PubMed 10843152]

141. Chesnut CH, Silverman S, Andriano K et al. A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the prevent recurrence of osteoporotic fractures study. PROOF Study Group. Am J Med . 2000; 109(4):267-76. [PubMed 10996576]

142. Cummings SR, Bates D, Black DM. Clinical use of bone densitometry: scientific review. JAMA . 2002; 288(15):1889-97. [PubMed 12377088]

143. Schneider D, Hofmann MT, Peterson JA. Diagnosis and treatment of Paget's disease of bone. Am Fam Physician . 2002; 65(10):2069-72. [PubMed 12046775]

144. US Department of Health and Human Services, Office of the Surgeon General. Bone health and osteoporosis: a report of the Surgeon General. Rockville, MD: US Department of Health and Human Services; 2004:218-53. Accessed 2005 Feb 8. [Web]

145. Upsher-Smith. Fortical^® (calcitonin-salmon [rDNA origin]) nasal spray prescribing information. Minneapolis, MN; 2006 Jun.

146. North American Menopause Society. Management of osteoporosis in postmenopausal women: 2006 position statement of the North American Menopause society. Menopause . 2006; 13:340-67. [PubMed 16735931]

147. Cosman F, de Beur SJ, LeBoff MS et al. Clinician's Guide to Prevention and Treatment of Osteoporosis. Osteoporos Int . 2014; 25:2359-81. [PubMed 25182228]

148. Watts NB, Bilezikian JP, Camacho PM et al. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the diagnosis and treatment of postmenopausal osteoporosis. Endocr Pract . 2010 Nov-Dec; 16 Suppl 3:1-37. [PubMed 21224201]

622. Buckley L, Guyatt G, Fink HA et al. 2017 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis. Arthritis Rheumatol . 2017; 69:1521-1537. [PubMed 28585373]