Continuing Education Activity

Salmon calcitonin, hereinafter referred to as calcitonin, is a derivative of human calcitonin utilized for the management of postmenopausal osteoporosis, Paget disease of bone, and hypercalcemia. Calcitonin is a peptide hormone consisting of 32 amino acids, primarily synthesized by the parafollicular cells (C cells) of the human thyroid gland. Extensive research has been conducted on salmon calcitonin, revealing its heightened potency compared to the human variant, thus establishing it as the preferred option in clinical application. The drug's clinical significance derives from its ability to inhibit osteoclast activity and increase renal excretion of calcium. Through these mechanisms, the resorption of bone matrix and serum calcium levels are diminished. Owing to these reasons, calcitonin proves advantageous in addressing the aforementioned conditions. This activity reviews the mechanism of action, adverse event profile, toxicity, dosing, pharmacokinetics, and monitoring recommendations of calcitonin to enhance the competence of interprofessional healthcare team members when caring for patients with postmenopausal osteoporosis, Paget disease of bone, and hypercalcemia.

Objectives:

• Identify the appropriate indications for calcitonin therapy, including postmenopausal osteoporosis, Paget disease of bone, and hypercalcemia.
• Screen patients for contraindications, allergies, and potential interactions before initiating calcitonin therapy.
• Implement proper patient dosing regimens based on specific clinical conditions and patient characteristics.
• Coordinate the patient care plan with the interprofessional team to manage potential drug interactions and optimize treatment outcomes.

Indications

Calcitonin was initially discovered in 1962 by Drs. Copp and Cheney who isolated and characterized the hormone from the ultimobranchial gland of fish. In subsequent years, calcitonin was identified in various other species, including mammals. The recognition of the drug's physiological role in calcium regulation led to the exploration of calcitonin's therapeutic potential of calcitonin. Calcitonin is a peptide hormone consisting of 32 amino acids, primarily synthesized by the parafollicular cells (C cells) of the human thyroid gland. The hormone exists in different forms, including salmon calcitonin, human calcitonin, and synthetic analog.

Extensive research has been conducted on salmon calcitonin, revealing its heightened potency compared to the human variant, thus establishing it as the preferred option in clinical application. Currently, the U.S. Food and Drug Administration approved calcitonin for the management of postmenopausal osteoporosis, Paget's disease of bone, and hypercalcemia. The drug's clinical significance derives from its ability to inhibit osteoclast activity and increase the renal excretion of calcium. These mechanisms diminish the resorption of bone matrix and serum calcium levels.

FDA-Approved Indications

Postmenopausal osteoporosis

Calcitonin is currently FDA-approved for treating postmenopausal osteoporosis, provided the patient has been in the postmenopausal phase for a minimum of 5 years.[1] By inhibiting osteoclasts, bone mineral density (BMD) losses can be mitigated, and the risk of osteoporotic fractures can be lowered. The 5-year "PROOF" study involving 1108 postmenopausal women demonstrated that a daily intake of 200 IU intranasal calcitonin led to a remarkable 33% reduction in the risk of new vertebral fractures. The lumbar spine BMD increased from 1% to 1.5% from the baseline, whereas the placebo group experienced a decrease in bone turnover. However, the risk of hip and other non-vertebral fractures remained unchanged.[2] In a phase 3 clinical trial known as Oral Calcitonin in Postmenopausal Osteoporosis (ORACAL), a total of 565 women between the ages of 46 and 86 were administered calcitonin. Notably, significant improvements in their lumbar, trochanteric, and femur bone mineral density (BMD) were observed, along with a reduction in markers indicative of bone resorption.[3] However, calcitonin exhibits comparatively lower efficacy than bisphosphonates in terms of elevating BMD and decreasing rates of bone turnover.[4] A slightly elevated incidence of malignancy has been observed in patients utilizing intranasal calcitonin instead of those receiving a placebo. Due to these factors, calcitonin is not considered a first-line treatment for postmenopausal osteoporosis, and the FDA suggests its use solely in situations where contraindications to alternative therapies are present.

However, short-term use of calcitonin has also been demonstrated to significantly reduce osteoporotic bone pain compared to a placebo, especially in the acute setting.[5][6] Therefore, calcitonin may be a preferred treatment for acute osteoporotic fractures. In such circumstances, physicians are advised to administer calcitonin until the pain diminishes. This is followed by transitioning to a more potent and enduring therapeutic option, such as bisphosphonate, for long-term management.

The recommended dosages of calcitonin for postmenopausal osteoporosis comprise 200 units of the medication administered through intranasal spray once daily or 100 units administered via intramuscular (IM) or subcutaneous (SQ) injection once daily. The patient should complement calcitonin intake with calcium and vitamin D supplementation. Monitoring BMD measurements is necessary every 1 to 2 years after initiating the calcitonin therapy. Furthermore, additional parameters such as height, weight, serum calcium, and serum calcifediol levels should be evaluated in the patient annually. Biochemical markers of bone turnover can also help assess the response to treatment.[7] Furthermore, the patient should be questioned about chronic back pain during each visit.

Paget disease of bone

Calcitonin is an FDA-approved medication and secondary treatment option for Paget disease of bone, prescribed when issues of bisphosphonate tolerance arise. Clinically, calcitonin can provide relief in bone pain, reverse neurological deficits, reduce blood flow to the diseased bone, and may even improve hearing loss associated with Paget disease.[8] Calcitonin therapy reaches its peak effect on osteoclasts within 24 to 48 hours, in contrast to bisphosphonate therapy, which takes 3 months to achieve maximal suppression of bone resorption.[9] This characteristic of calcitonin makes the drug a preferred choice in situations where prompt surgery on the Pagetic bone is imperative.

In a study involving 24 patients with untreated Paget disease of bone, calcitonin administration reduced skeletal blood flow to the affected Paget bone. This effect could lead to decreased disease activity and lessened bleeding during surgical interventions. The markers of bone remodeling and turnover, namely serum alkaline phosphatase (ALP) and urine hydroxyproline, were also reduced.[10] A separate study involving 85 patients similarly exhibited 50% reductions in ALP and urine hydroxyproline levels over 3 to 6 months. However, among these individuals, 22 reverted to baseline values despite continuous treatment. Interestingly, out of these 22 patients, 19 developed elevated titers of anti-calcitonin antibodies.[11]

This phenomenon reduces the long-term effectiveness of calcitonin in a substantial number of patients. In contrast, bisphosphonates are not susceptible to antibody formation and have demonstrated greater anti-resorptive effects. Due to the extended half-life within the Paget bone, bisphosphonates effectively suppress disease activity for years, even after treatment cessation.[12] Although bisphosphonates are a better option for long-term management, calcitonin may be better suited for providing acute relief from Paget-associated bone pain.[13][8] 

As Paget's disease of bone is a chronic condition, calcitonin therapy can be sustained indefinitely. Patients are initially administered 50 to 100 units of calcitonin daily through IM or SQ administration, followed by a maintenance dose of either 50 units daily or 50 to 100 units every 1 to 3 days. Serum ALP should be measured at 3 to 6 months to assess patients' response to calcitonin therapy. When serum ALP levels have returned to normal, they can be evaluated every 6 months to a year. If ALP levels start to increase again, the possibility of calcitonin antibody formation should be considered; therefore, an antibody titer test may be warranted. Calcium and vitamin D supplementation are also recommended for patients, followed by periodic monitoring of their serum levels. If the patient continues to experience bone pain despite calcitonin therapy, obtaining a computed tomography (CT) or magnetic resonance imaging (MRI) scan can provide more precise insight into the lesion and aid in deciding whether surgical intervention should be considered.

Hypercalcemia

Calcitonin is an FDA-approved medication for the treatment of hypercalcemic emergencies. The complications associated with hypercalcemia include confusion, coma, dehydration, polyuria, kidney stones, nausea, constipation, pancreatitis, hypertension, and cardiac arrhythmias. Calcitonin addresses these concerns by decreasing the resorption of hydroxyapatite from bone and enhancing the renal excretion of calcium. Owing to the drug's swift onset of action, calcitonin is a viable treatment option when a prompt reduction in calcium levels is required.

The initial reduction in calcium levels is achieved through rehydration using a saline solution, followed by the simultaneous administration of bisphosphonate and calcitonin. Calcitonin is administered through IM or SQ injection at a dosage of 4 units per kg, repeated every 12 hours.[14] Calcitonin's effects become noticeable within approximately 2 hours, and it can reduce serum calcium levels by up to 1 to 2 mg/dL within 4 to 6 hours.[15] If the response is inadequate after 12 hours, the dosage can be increased to 4 units per kg. If the initial response proves inadequate after 48 hours, the administration of calcitonin can be increased to every 4 hours. After 24 to 48 hours, the effects of calcitonin become less effective as osteoclasts partially adapt to its action, reducing the drug's calcium-lowering efficacy.[16][17][18]

The countermeasure to counteract this adaptation mechanism involves simultaneously administering a bisphosphonate. As bisphosphonates attain effective concentrations within 48 hours, their efficacy increases while calcitonin's effectiveness declines. Calcitonin can also combine with other calcium-lowering drugs, including loop diuretics, oral phosphate, and corticosteroids.

Off-Label Uses

• Migraine headaches: Research indicated that intranasal or SQ administration of calcitonin may provide relief from migraine pain, potentially by inhibiting the release of neuropeptides involved in migraine pathogenesis. However, the available evidence supporting its efficacy is limited.
• Acute bone loss due to sudden immobilization: Calcitonin might aid in averting or mitigating the rapid loss of BMD that occurs when an individual becomes immobilized due to injury, surgery, or illness.

Mechanism of Action

Endogenous calcitonin is synthesized in the parafollicular cells (C cells) of the thyroid gland, whereas exogenously administered calcitonin extract originates from the ultimobranchial gland of salmon. Salmon calcitonin is a 32-amino acid, alpha-helical polypeptide that differs significantly from human calcitonin, particularly in amino acids 10 to 27. These variations in the amino acid sequence account for the heightened potency observed in salmon-derived calcitonin.[19][20][21][22] Calcitonin functions through a G protein–coupled receptor, known as the calcitonin receptor, which predominantly transmits signals via the cAMP and PLC/IP3 pathways.[19][23]

Calcitonin exerts its most significant physiological effects on osteoclasts and the tubular epithelium of kidneys, which hold clinical relevance. In the tubules, calcitonin induces diuresis and decreases reabsorption, reducing serum calcium and phosphate levels. In bone, calcitonin prompts osteoclast contraction, thereby diminishing their motility and capacity to resorb bone. Osteoclasts are recognized to undergo retraction and escape the sustained impacts of calcitonin administration within 24 to 48 hours, thereby reducing its long-term potency. Calcitonin also inhibits carbonic anhydrase II, disrupting the optimal acidic environment necessary for osteoclast activity. Furthermore, calcitonin hinders the differentiation of osteoclast precursors into their mature form.[19][20] This cumulative effect reduces bone matrix resorption and lowers serum calcium levels, albeit with diminishing efficacy over 1 to 2 days.

Pharmacokinetics

Absorption: Calcitonin is available in different formulations, including nasal spray and SQ and IM injections. The bioavailability of calcitonin varies depending on the route of administration. Intranasal administration leads to gradual absorption, with peak plasma concentrations attained within 15 to 40 minutes and a 3% bioavailability. SQ and IM injections yield peak plasma concentrations within 15 to 30 minutes and bioavailability of approximately 66%.

Distribution: Calcitonin disperses throughout the body following its absorption. The drug exhibits a relatively short half-life, ranging from minutes to hours. Calcitonin readily attaches to plasma proteins, primarily albumin, at a rate of approximately 30% to 40%. The drug distributes across various body tissues, with the highest concentrations observed in the kidneys, bones, and central nervous system. In addition, calcitonin displays a volume of distribution ranging from 0.15 to 0.3 L/kg.

Metabolism: The primary metabolic processes for calcitonin involve enzymatic breakdown by proteolytic enzymes, which predominantly occur in the kidneys and other tissues. 

Elimination: Calcitonin and its metabolites are excreted from the body via urine and feces.

Administration

Available Dosage Forms

Patients can administer calcitonin through a nasal spray or SQ or IM injection. All these formulations are rapidly absorbed in the body and exhibit an onset of action within less than 30 minutes.

Strength

The strength of calcitonin varies depending on the administration method. For SQ and IM injections, the available strength of the medication is 200 IU/mL. When using the nasal spray, each actuation delivers 200 IU of calcitonin.

Adult Dosage

The injectable solution of calcitonin has a concentration of 200 units/mL, whereas the nasal solution delivers 200 units per actuation. Nasal administration of the medication offers a bioavailability of only 25% of the injectable form and is characterized by a slower absorption rate. In the injectable form, the SQ route is preferred for volumes less than 2 mL, whereas the IM route is recommended for volumes exceeding 2 mL. Self-administration through the SQ route or intranasal spray is recommended in an outpatient setting. Both intranasal spray and injectable forms are viable options for treating postmenopausal osteoporosis. Nevertheless, the injectable form is the preferred choice when addressing conditions such as Paget disease of bone and hypercalcemia. Patients should be provided with supplementary calcium at a dosage of 1000 mg/d and vitamin D at a dosage of 400 IU/d alongside calcitonin therapy.[24][25][26] Oral administration of calcitonin is currently being investigated, and preliminary results are promising.[3] 

Adult dosages of calcitonin for managing postmenopausal osteoporosis, Paget disease of bone, and hypercalcemia are listed below.

• Postmenopausal osteoporosis: For SQ or IM administration, 100 IU of the medication should be taken daily. The nasal spray option requires alternating nostrils daily and using 200 units per actuation.
• Paget disease of bone: The recommended initial dosage is 100 IU daily through SQ or IM injection. A daily dosage of 50 IU or a range of 50 to 100 IU every 1 to 3 days is advised for maintenance.
• Hypercalcemia: The initial dosage is typically 4 IU/kg administered every 12 hours via SQ or IM injection. If the response is inadequate, the dosage can be increased up to 8 IU/kg every 6 hours.

Specific Patient Population

Hepatic impairment: As the kidneys and other tissues primarily metabolize calcitonin, not the liver, dosage adjustments are unnecessary for patients with hepatic impairment.

Renal impairment: As calcitonin and its metabolites are excreted via the urine, renal impairment can influence their clearance and elevate their exposure, possibly resulting in a prolonged half-life. However, no dosage adjustments are required for patients with mild-to-moderate renal impairment. 

Pregnancy considerations: The available data on using calcitonin during pregnancy are limited. Although animal studies have not indicated any fetal harm, the data from human studies is insufficient to establish the drug's safety for use in pregnancy.

Breastfeeding considerations: The available data on the effects of calcitonin on nursing infants are limited. Consequently, even the nasal spray option of calcitonin is not recommended for breastfeeding mothers due to insufficient information.

Pediatric patients: The safety and effectiveness of calcitonin in pediatric populations have not been confirmed. Limited data exist regarding the use of calcitonin in children. Calcitonin could potentially disrupt bone growth and development in children and adolescents. Consequently, this drug is not approved or recommended for pediatric patients.

Older patients: No dosage adjustment is necessary for older patients based solely on their age. However, older individuals might be more sensitive to the effects of calcitonin and could encounter increased adverse reactions, such as hypocalcemia, nausea, and flushing.

Adverse Effects

Patients with allergies to fish products may be at an increased risk of experiencing hypersensitivity reactions when using salmon calcitonin. The hypersensitivity reactions observed in patients include bronchospasm, tongue swelling, and anaphylactic shock. Patients who were administered salmon calcitonin reported isolated instances of maculopapular rashes and urticaria. A skin allergy test is advisable for individuals predisposed to atopy before administering the drug. In cases of such reactions, epinephrine injection serves as the rescue therapy.[27]

Clinicians should exercise particular caution when treating patients with bipolar disorder, as calcitonin can potentially lower serum lithium levels. Animal studies indicate that administering calcitonin during pregnancy could reduce fetal weight. Although data from human studies do not align with this finding, it might still be advisable to exercise additional caution when considering calcitonin therapy during pregnancy.[27]

The prevalent adverse effects associated with parenterally administered calcitonin pertain to the gastrointestinal (GI) tract. Approximately 10% of patients encountering this route of administration may experience mild nausea, which subsides as the therapy progresses. Other GI adverse effects include reduced appetite, diarrhea, abdominal pain, and discomfort. Injectable calcitonin can cause flushing of the face, hands, and feet several minutes after administration. Moreover, a localized inflammatory reaction might also occur at the injection site. Other adverse effects of injectable calcitonin include pruritus, tingling of the palms and soles, and increased diuresis.

The nasal spray formulation can lead to epistaxis, rhinitis, and ulceration of the nasal mucosa. As a result, it is essential to thoroughly examine the nasal mucosa, turbinates, and septum before initiating the therapy, whenever the patient reports nasal symptoms during the therapy, and periodically during the treatment procedure. The incidence of adverse nasal events increases with the patient's age. If nasal ulceration exceeds a diameter of 1.5 mm, the suggested course of action is to discontinue using the nasal formulation. Nausea may also arise from intranasal calcitonin use, although its occurrence is less frequent when compared to parenteral administration.[28]

Drug-Drug Interactions

Medications that may interact with calcitonin include etelcalcetide, foscarnet, lithium, sincalide, and zoledronic acid. These medications can impact patients' calcium levels or kidney function using calcitonin. Such interactions may increase the risk of adverse effects or diminish the efficacy of calcitonin treatment. 

Contraindications

Hypersensitivity: Calcitonin is contraindicated in individuals with known hypersensitivity or allergic reactions to the drug or its components. Hypersensitivity reactions can manifest as mild skin responses or escalate to severe anaphylaxis.

Box Warning

The FDA has not issued any specific Box Warnings for calcitonin. Notably, drug safety information can evolve over time.

Precautions 

Hypocalcemia: Calcitonin can decrease serum calcium levels by inhibiting bone resorption, leading to adverse effects such as tetany, muscle cramps, and cardiac arrhythmias. Therefore, hypocalcemia must be rectified before initiating calcitonin treatment in patients, and monitoring is also recommended throughout the therapy. In addition, to address this concern, patients should be provided with supplementary calcium at 1000 mg/d and vitamin D at 400 IU/d.

Monitoring

Patients receiving calcitonin should be monitored for indications of hypersensitivity reactions, including anaphylaxis, and for the potential occurrence of hypocalcemia.

Toxicity

A weak association is observed between the extended usage of intranasal calcitonin and an increased incidence of cancer, particularly basal cell carcinoma. A comprehensive meta-analysis of 21 randomized, controlled clinical trials unveiled a higher occurrence of malignancy in individuals treated with calcitonin (4.1%) compared to those administered a placebo (2.9%).[1][29]

Animal studies have demonstrated an increased incidence of pituitary hyperplasia and adenomas with high calcitonin dosages. However, preclinical investigations involving the overexpression of salmon calcitonin in transgenic mice have not provided any indication of the molecule acting as a carcinogen.[30] Calcitonin has also demonstrated the absence of mutagenic properties when exposed to Salmonella and Escherichia coli cells. Furthermore, based on the current comprehension of calcitonin's mechanisms of action, there is no plausible mechanism of causality.[31][32] Although the association between calcitonin usage and cancer remains tenuous, it is advisable to carefully contemplate treatment alternatives with more favorable risk-to-benefit profiles before initiating pharmacotherapy.

Considering calcitonin's mechanisms of action, the drug may also induce hypocalcemia. Hypocalcemia can trigger symptoms such as tetany, seizures, changes in mental status, and even cardiac arrest. Patients should incorporate supplementary vitamin D and calcium into their regimen when utilizing calcitonin to manage Paget disease of bone or postmenopausal osteoporosis to avert the onset of hypocalcemia. Men between the ages of 50 and 70 should consider a daily calcium intake of 1000 mg, whereas women older than 50 and men older than 70 should take 1200 mg of calcium daily. Individuals aged 50 or older should take 800 to 1000 units of vitamin D daily, whereas those aged 70 or older should reduce their daily vitamin D intake to 800 units.[1] Combining calcitonin and bisphosphonates can offer therapeutic advantages in managing hypercalcemia. However, this approach necessitates caution, as it can potentially lead to hypocalcemia, especially when using zoledronate.[33]

Enhancing Healthcare Team Outcomes

When initiating calcitonin therapy for patients with acute hypercalcemia, Paget disease of bone, and postmenopausal osteoporosis, a collaborative healthcare approach involving an interprofessional team is essential. This healthcare team should include the patient's primary care physician, endocrinologist, oncologist, advanced practice practitioners, nursing staff, and clinical pharmacist to provide a comprehensive approach toward patient care. 

Close monitoring of patients' conditions is crucial throughout calcitonin therapy to uphold the safety of patients and enhance their treatment outcomes. Interprofessional collaboration facilitates consistent monitoring of the patient's treatment response, encompassing evaluations of bone density, serum calcium levels, and the occurrence of adverse effects. Effective communication and coordination with shared decision-making among healthcare professionals enable timely modifications in dosage, treatment duration, or adjunctive therapies when necessary. This approach optimizes the medication's potential therapeutic effectiveness while minimizing adverse events.