Continuing Education Activity

Salmon calcitonin (after this referred to as “calcitonin”) is an analog of human calcitonin used to treat postmenopausal osteoporosis, Paget disease of bone, and hypercalcemia. Its clinical importance derives from its ability to inhibit osteoclasts and increase renal excretion of calcium. Through these processes, bone matrix resorption and serum calcium are both decreased. For these reasons, it is of benefit in the treatment of postmenopausal osteoporosis, Paget disease of bone, and emergent hypercalcemia. This activity reviews the mechanism of action, adverse event profile, toxicity, dosing, pharmacodynamics, and monitoring of calcitonin, pertinent for clinicians and other interprofessional team members where calcitonin therapy can provide patient benefit.

Objectives:

• Identify the mechanism of action of calcitonin.
• Review the FDA-approved on-label indications of calcitonin.
• Summarize the contraindications and risks associated with calcitonin therapy.
• Outline the importance of collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients receiving treatment with calcitonin.

Indications

Salmon calcitonin (after this referred to as “calcitonin”) is an analog of human calcitonin used in the treatment of postmenopausal osteoporosis, Paget disease of bone, and hypercalcemia. Its clinical importance derives from its ability to inhibit osteoclasts and increase renal excretion of calcium. Through these processes, bone matrix resorption and serum calcium are both decreased. For these reasons, it is of benefit in the treatment of postmenopausal osteoporosis, Paget disease of bone, and emergent hypercalcemia.

Postmenopausal Osteoporosis

Calcitonin is currently FDA approved for use in postmenopausal osteoporosis once the patient is at least five years postmenopausal.[1] By inhibiting osteoclasts, mitigation of bone mineral density (BMD) losses can occur, and the risk of osteoporotic fractures decreased. The 5-year “PROOF” study of 1,108 postmenopausal women showed that taking 200 IU intranasal calcitonin per day reduced the risk of new vertebral fractures by 33%. Lumbar spine BMD increased 1 to 1.5% from baseline, and it decreased bone turnover compared to placebo groups. The risk of hip and other non-vertebral fractures remained unchanged.[2] A phase 3 clinical trial of 565 women (ORACAL) 46 to 86 years old who took calcitonin showed increased lumbar, trochanteric, and femur BMD and decreased markers of bone resorption.[3] However, calcitonin is less effective than bisphosphonates at increasing BMD and reducing rates of bone turnover.[4] There is a slightly increased incidence of malignancy in patients using intranasal calcitonin vs. those using a placebo. For these reasons, calcitonin is not a first-line treatment for postmenopausal osteoporosis, and the FDA only recommends use when contraindications to other therapies exist.

However, short-term use of calcitonin has also been demonstrated to significantly reduce osteoporotic bone pain compared to placebo, especially in the acute setting.[5][6] Therefore, calcitonin may nonetheless be a preferred treatment in cases of acute osteoporotic fracture. In such an event, the recommendation is for calcitonin use until the pain has subsided and then to switch over to a more effective long-term drug, such as a bisphosphonate.

Recommended dosages are 200 units via intranasal spray once daily or 100 units once daily via intramuscular (IM)/subcutaneous (subQ) injection. The patient should supplement calcitonin with calcium, and vitamin D. BMD measurements should occur every 1 to 2 years after beginning therapy. Height, weight, serum calcium, and serum calcifediol should be measured yearly. Biochemical markers of bone turnover can also be useful to assess therapeutic response.[7] The patient should be questioned about chronic back pain every visit.

Paget Disease of Bone

Calcitonin is an FDA-approved second-line treatment for Paget disease, indicated when bisphosphonate tolerance is a problem. Clinically, it can relieve bone pain, reverse neurologic deficits, reduce blood flow to diseased bone, and may even improve Pagetic hearing loss.[8] Calcitonin therapy has a peak effect on osteoclasts at 24 to 48 hours, while bisphosphonate therapy requires three months to maximally suppress bone resorption.[9] Therefore, it is also preferable when prompt surgery on Pagetic bone is necessary.

In a study of 24 patients with untreated Paget’s disease, treatment with calcitonin showed reduced skeletal blood flow to Pagetic bone, which may lower disease activity and reduce bleeding during surgery. Serum alkaline phosphatase (ALP) and urine hydroxyproline, markers of bone remodeling and turnover, were also reduced.[10] Another study of 85 patients similarly showed 50% decreases in ALP and urine hydroxyproline over 3 to 6 months. However, 22 of these patients returned to baseline despite continuous treatment. Interestingly, 19 of these 22 patients developed high titers of anti-calcitonin antibodies.[11] This phenomenon reduces the long-term effectiveness of calcitonin in a substantial number of patients. By comparison, bisphosphonates are not subject to antibody formation and have demonstrated greater anti-resorptive effects. Due to a long half-life in bone, bisphosphonates also suppress disease activity for years after treatment has ended.[12] Though bisphosphonates are a better choice for long-term management, calcitonin may be better-suited for acute relief of Paget-associated bone pain.[13][8] 

Paget disease of bone is a chronic illness; therefore, calcitonin therapy can be of indefinite duration. Patients are initially given 50 to 100 units of calcitonin daily via IM or subQ administration and then given either 50 units daily or 50 to 100 units every 1 to 3 days. Serum alkaline phosphatase should be measured at 3 to 6 months to assess for a response to therapy. After serum ALP has normalized, it can be measured every six months to one year. If ALP once again begins to rise, the formation of calcitonin antibodies should be suspected, and ordering an antibody titer may be warranted. Calcium and vitamin D supplementation are also recommendations, and their serum levels should be intermittently measured. If the patient has bone pain refractory to calcitonin therapy, a CT scan or MRI can help to define the lesion better and determine whether surgical management should be a consideration.

Hypercalcemia

Calcitonin is FDA approved for the treatment of hypercalcemic emergencies. Complications of hypercalcemia include confusion, coma, dehydration, polyuria, kidney stones, nausea, constipation, pancreatitis, hypertension, and cardiac arrhythmias. Calcitonin addresses this problem by decreasing bone resorption of hydroxyapatite and increasing renal excretion of calcium. Since calcitonin is fast-acting, it is a viable therapeutic choice when a rapid decrease in calcium is needed.

Calcium initially lowers via rehydration with a saline solution, followed by co-administration of a bisphosphonate and calcitonin. Calcitonin administration is via IM or SubQ injection at a rate of 4 units/kg every 12 hours.[14] It takes effect in about 2 hours and can lower serum calcium 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 increase to 4 units/kg. If the response remains inadequate after 48 hours, calcitonin administration can be every 4 hours. After 24 to 48 hours, the osteoclasts partially escape the action of calcitonin, and the drug’s calcium-lowering properties diminish.[16][17][18] The countermeasure for this escape mechanism is via concurrent administration of a bisphosphonate. Since bisphosphonates reach effective dosages after 48 hours, their activity ramps up as calcitonin’s activity declines. Calcitonin can also combine with other calcium-lowering drugs, including loop diuretics, oral phosphate, and corticosteroids.

Mechanism of Action

Endogenous calcitonin is produced in the parafollicular C cells of the thyroid gland, while exogenously administered calcitonin extract derives from the ultimobranchial gland of salmon. Salmon calcitonin is a 32 amino acid, alpha-helical polypeptide that differs significantly from human calcitonin along amino acids 10 to 27. These differences in amino acid sequence explain the increased potency of salmon-derived calcitonin.[19][20][21][22] It acts on a G protein-coupled calcitonin receptor, which primarily transduces signals via the cAMP and PLC/IP3 pathways.[19][23] Calcitonin has its most clinically important physiologic effects on osteoclasts and the tubular epithelium of the kidney. In the tubules, it reduces serum calcium and phosphate by promoting diuresis and decreasing reabsorption. In bone, it causes osteoclasts to contract, which reduces their motility and ability to resorb bone. Osteoclasts are known to subsequently retract and “escape” the effects of continuously administered calcitonin within 24-48 hours, reducing its long-term potency. It also causes inhibition of carbonic anhydrase II, which disrupts the acidic environment that is optimal for osteoclast activity. Additionally, calcitonin prevents osteoclast precursors from differentiating into their mature form.[19][20] The net effect of this is a decrease in the resorption of bone matrix and reduced serum calcium, but with decreasing effectiveness in 1 to 2 days.

Administration

Calcitonin administration can be via injection (subQ/IM) or nasal spray. All forms are rapidly absorbed and have an onset of action of fewer than 30 minutes. The injectable solution contains 200 units/mL, while the nasal solution contains 200 units/actuation. Nasal administration has only 25% of the bioavailability of the injectable form and is absorbed more slowly. In its injectable form, the subQ route is the choice when the volume is less than 2mL. IM injections are a viable choice when the volume exceeds 2mL. SubQ self-administration or intranasal spray is preferable in an outpatient setting. Either the intranasal spray or injectable form may be used for postmenopausal osteoporosis. However, the injectable form is preferred for the treatment of Paget disease and hypercalcemia.[24][25][26] Oral administration is currently under investigation with promising results.[3]

Adverse Effects

Patients with allergies to fish products may be prone to hypersensitivity reactions when taking salmon calcitonin. The hypersensitivity response includes bronchospasm, tongue swelling, and anaphylactic shock. Reports of isolated incidences of maculopapular rashes and urticaria also exist. In atopy-prone individuals, a skin allergy test is necessary before drug administration; rescue therapy for such a reaction is via epinephrine injection. Clinicians must also exercise special care for patients being treated for bipolar disorder as calcitonin can decrease serum lithium. Animal research shows decreased fetal weight with the administration of calcitonin during pregnancy. While this has not been the case in humans based on data, it may nonetheless be prudent to exercise additional caution with calcitonin therapy during pregnancy.[27]

The most common side effects of parenterally administered calcitonin involve the GI tract; 10% of such patients experience mild nausea that subsides as therapy continues. Other GI side effects include reduced appetite, diarrhea, abdominal pain, and discomfort. Injectable calcitonin can cause flushing of the face, hands, and feet several minutes after administration. A local inflammatory reaction may also occur at the site of injection. Other side effects of injectable calcitonin include pruritus, tingling of the palms and soles, and increased diuresis.

The nasal spray can cause epistaxis, rhinitis, and ulceration of the nasal mucosa. Therefore, the nasal mucosa, turbinates, and septum should be closely inspected before beginning therapy, whenever the patient presents with nasal symptoms, and periodically throughout treatment. Adverse nasal events increase with the age of the patient. When nasal ulceration exceeds a 1.5 mm diameter, the recommendation is to discontinue the nasal formulation. Nausea may also occur with intranasal calcitonin but with decreased incidence compared to parenteral administration.[28]

Toxicity

There is a weak association between long-term use of intranasal calcitonin and increased incidence of cancer, particularly basal cell carcinoma. A meta-analysis of 21 randomized, controlled clinical trials showed an increased incidence of malignancy in patients treated with calcitonin (4.1%) compared to patients using a placebo (2.9%).[1][29] Animal studies have demonstrated an increased incidence of pituitary hyperplasia and adenomas with high dosages of calcitonin, but preclinical studies that induced overexpression of salmon calcitonin in transgenic mice showed no evidence of the molecule acting as a carcinogen.[30] Nor has it shown mutagenic qualities when introduced to Salmonella and E. coli cells. Furthermore, there is no plausible mechanism of causality based on the current understanding of calcitonin’s mechanisms of action.[31][32] While the association between calcitonin usage and cancer is weak, it is nonetheless prudent to consider treatment alternatives with better risk/benefit profiles before initiating pharmacotherapy.

Given its mechanisms of action, the use of calcitonin may also contribute to hypocalcemia. Hypocalcemia can trigger tetany, seizures, changes in mental status, and cardiac arrest. When using calcitonin for Paget disease or osteoporosis, recommendations that patients take supplemental vitamin D and calcium to prevent hypocalcemia. Men 50 to 70 years old should take 1,000 mg of calcium per day, while women older than 50 and men older than 70 should take 1200 mg per day. Patients over 50 should ingest 800 to 1000 units of vitamin D per day, and patients older than 70 should reduce intake to 800 units per day.[1] The use of calcitonin and bisphosphonates in tandem can be of therapeutic benefit when treating hypercalcemia. However, this should be done with care as it can also trigger hypocalcemia, most notably when the bisphosphonate is zoledronate.[33]

Enhancing Healthcare Team Outcomes

In patients with acute hypercalcemia, Paget disease of bone, and osteoporosis, introducing calcitonin therapy should involve the efforts of an interprofessional healthcare team that includes the patient's primary care clinician (MD, DO, PA, NP), endocrinologist, oncologist, nursing staff, and a board-certified pharmacotherapy pharmacist to provide a comprehensive approach towards patient care. Each interprofessional team member will contribute with the expertise from their discipline and must communicate with other team members to keep everyone apprised of the patient's progress or lack thereof. This will optimize the potential therapeutic effectiveness of the medication while minimizing adverse events. [Level 5]