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.
Calcitonin is currently FDA approved for use in postmenopausal osteoporosis once the patient is at least five years postmenopausal. 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. 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. However, calcitonin is less effective than bisphosphonates at increasing BMD and reducing rates of bone turnover. 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 demonstrated to significantly reduce osteoporotic bone pain compared to placebo, especially in the acute setting. 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 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. The patient should be questioned about chronic back pain every visit.
Paget’s 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. Calcitonin therapy has a peak effect on osteoclasts at 24 to 48 hours, while bisphosphonate therapy requires three months to maximally suppress bone resorption. 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. 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. 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. Though bisphosphonates are a better choice for long-term management, calcitonin may be better-suited for acute relief of Paget’s-associated bone pain.
Paget’s 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.
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. 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. 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. The countermeasure for this escape mechanism is via concurrent administration of a bisphosphonate. Since bisphosphonates reach effective dosages after 48 hours, its activity ramps up as calcitonin’s activity declines. Calcitonin can also combine with other calcium-lowering drugs, including loop diuretics, oral phosphate, and corticosteroids.