Calcitonin

Mechanism of Action
Calcitonin is a polypeptide hormone secreted by the parafollicular cells of the thyroid gland. It is secreted in response to high circulating levels of ionized calcium, and inhibits osteoclast-mediated bone resorption through a direct effect on the osteoclasts.³²

Since parathyroid hormone stimulates osteoclast-mediated bone resorption, calcitonin may be thought of as having the opposite effect to parathyroid hormone.³³

Available Formulations and Indications ⁶

Both the injectable and intranasal formulations of calcitonin are approved by the FDA in the US for the treatment of postmenopausal osteoporosis. The indication for intranasal calcitonin states that it should only be used in women who are more than five years past menopause and who refuse or cannot tolerate estrogens or in whom estrogens are contraindicated.⁶

Effects on BMD and Fracture Reduction
Evaluation of calcitonin's clinical efficacy is made difficult by the wide range of study populations and dosage regimens used in clinical trials. Studies evaluating the effect of injectable calcitonin in preventing the development of postmenopausal osteoporosis have had conflicting results. Intranasal calcitonin has not been shown to have a significant effect on early postmenopausal bone loss.³³

Prevent Recurrence of Osteoporotic Fractures (PROOF) is a five-year prospective study ³⁴ evaluating the effects of calcitonin on fracture rates. This study involves 1255 postmenopausal women in the United States and United Kingdom (average age 68 years) with established osteoporosis. All patients had low bone mass and a history of vertebral compression fractures. All patients received daily supplements of 1000 mg elemental calcium and 400 IU vitamin D. Patients were randomized to placebo or nasal calcitonin (100, 200, or 400 IU/day). The 200-IU dose of salmon calcitonin nasal spray significantly reduced the risk of new vertebral fractures by 33% compared with placebo (RR, 0.67; 95% CI, 0.47-0.97).

The PROOF study has several shortcomings.³⁵ There was a 36% reduction in risk of vertebral deformities in the group that received 200 IU a day, but no significant effects were seen with a higher dose. There was no consistent reduction in the risk of other types of fractures across doses. By far the most important problem with the PROOF is that 59% of participants who were originally enrolled were "lost to follow-up." Moreover, the trial was only partly blinded: doctors and their patients with osteoporosis saw the results of bone density testing as the trial went along, consequently many investigators withdrew patients from the trial based on disappointing results of the drug on BMD.

So the question: Where does nasal calcitonin fit in the post-PROOF era? As presented here, second-generation bisphosphonates and raloxifene have greater or at least better-proven effectiveness in reducing the risk of fracture. The effectiveness of estrogen has become controversial and needs to be resolved by a large well-done trial. Nasal calcitonin appears to have a small effect on bone density and, perhaps, a modest effect on the risk of vertebral fracture in women with osteoporosis.

Side-Effects ⁶, ³⁶

Injectable calcitonin is characterized by a number of systemic side effects, including nausea and gastric discomfort. Fortunately, it appears that these symptoms tend to decrease in severity or disappear with continued treatment. These symptoms may be minimized by administering the drug at least four to five hours after a meal, preferably at bedtime. Facial flushing, dermatologic hypersensitivity, and local injection site reactions may also occur. Serious allergic reactions have been reported, although rare; skin testing is recommended for individuals in whom an allergy is suspected.

Intranasal calcitonin has a much lower rate of adverse effects than the injectable formulation, and is more acceptable to patients. The most commonly reported side effects relate to the nose, and include rhinitis, nasal symptoms, epistaxis, and headache. Rarely, patients will develop nasal ulcerations. For this reason, the manufacturer recommends periodic examination of the nostrils.³⁶

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