Drug Profile

Calcitonin is a hormone produced by the thyroid glands of mammals and fish. Synthetic forms have been made of the hormones from humans, pigs, salmon, and eels. Calcitonin is used to treat moderate to severe Paget’s disease, high levels of calcium in the blood (such as occur with cancer), and osteoporosis in women five years or more after menopause.

The regulatory history of calcitonin in the treatment of postmenopausal osteoporosis provides a rare insight into drug regulation at the Food and Drug Administration (FDA).[1] Keep the following facts in mind as you read the calcitonin history:

FDA guidelines issued in 1994 emphasized documenting the efficacy of a drug in reducing fractures before it is approved for the treatment of osteoporosis. Since 1995, the FDA has approved three drugs under these guidelines, alendronate (FOSAMAX), raloxifene (EVISTA), and risedronate (ACTONEL), for the treatment of osteoporosis. Note that conjugated estrogens are no longer approved for the treatment of postmenopausal osteoporosis.

Approximately 2.8 million prescriptions for calcitonin nasal spray were dispensed in 2003 at a retail cost of over $200 million, without evidence that the drug reduces the risk of fracture.

In the late 1970s, a new drug application (NDA) was submitted to the FDA, seeking approval of injectable calcitonin for treatment of postmenopausal osteoporosis. The FDA’s review of the clinical data submitted by the company was not favorable, and the drug was not approved. Although there was a suggestion that daily subcutaneous (under the skin) or intramuscular injections of 100 international units (IU) of calcitonin increased total body calcium as compared with no treatment, the fact that the drug had no effect on bone mineral content in the radius (the small forearm bone) was of concern to FDA scientists.

The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee, made up of outside advisors, met in the autumn of 1981 to review calcitonin’s NDA. The drug’s failure to increase bone mineral content of the radius (forearm) was judged to be expected, since calcitonin’s effect was most pronounced in the type of bone found in the vertebrae of the spine, and the radius was known to be composed mostly of a different type of bone. The advisory committee dismissed any potential clinical relevance of calcitonin’s failure to increase mineral content of the radius.

The committee next shifted its attention to the effect of calcitonin on total body calcium. Concern was expressed about the decreased rate of accrual of total body calcium during the second year of treatment with calcitonin. Several members of the committee were also uneasy about the absence of fracture data and questioned the legitimacy of total body calcium as a “surrogate endpoint” (a fill-in) for actual evidence that the drug reduced fracture risk.

As a vote on approval of calcitonin drew near, a spokesman for the company asked the FDA if the advisory committee could suggest that approval be contingent on the company agreeing to do a phase IV (post-approval) study examining the effects of calcitonin on fractures. A senior FDA member reminded the advisory committee that recommendations for a new drug’s approval should be based on the available evidence. Phase IV [post-approval] studies were not intended to be used to “clarify substantial points of safety and effectiveness.”

Half the committee members present voted yes and half no when asked if evidence supported approval of calcitonin for the treatment of osteoporosis. Through the efforts of the chairman it was learned that a member of the committee who left the meeting early was in favor of calcitonin’s approval.

The FDA approved calcitonin in 1984 for treatment of postmenopausal osteoporosis subject to a phase IV study. Within a year, a phase IV fracture study was under way. After four years, only 151 of the proposed 300 women had been enrolled, and 77 of those had dropped out of the study. An early analysis of the study found an imbalance between the calcitonin and control groups in the average number of vertebral fractures at the beginning of the study. A vertebral fracture may not be noticed clinically and may only be identified in a spinal X-ray. The results from this study were deemed unreliable, and calcitonin’s efficacy in reducing fracture remained unknown. After the failed fracture study, the company decided against attempting a second one. The use of injectable calcitonin for osteoporosis has since declined.

By the early 1990s, the development of calcitonin nasal spray was under way by Novartis. The company sponsored a large clinical trial known as the Prevent Reoccurrence of Osteoporotic Fractures, or PROOF trial. This five-year trial compared the effects of 100 IU, 200 IU, and 400 IU of calcitonin nasal spray to a placebo on incidence of vertebral fractures.

In 1994, another FDA advisory committee met to discuss the results from studies of calcitonin nasal spray, but not the yet-to-be-completed PROOF trial. The results from five clinical trials lasting one to two years and including about 550 patients were presented to the committee. The advisory committee found that the potential benefits of calcitonin nasal spray outweighed the potential risks and recommended its approval.

The FDA subsequently approved the drug for the treatment of postmenopausal osteoporosis in women who were more than five years postmenopausal. The drug’s professional product labeling or package insert plainly stated that “the evidence of efficacy [was] based on increases in spinal bone mineral density,” not fracture data.

Reports from small studies began to be published of calcitonin’s efficacy in reducing the risk of fractures. One study reported an increased risk of fracture in patients receiving calcitonin. Then, after 20 years of anticipation for conclusive proof that calcitonin reduces the risk of fracture, the results of the PROOF trial were finally published in late 2000.[2]

The results of the PROOF trial were disappointing. Although the 200 IU dose of calcitonin nasal spray was found to statistically significantly decrease risk of new vertebral fractures, no fracture efficacy was shown for the 100 IU or 400 IU dosages. However, the 400 IU dose was the only dose associated with a significant increase in spinal bone mineral density. A National Institutes of Health osteoporosis consensus panel summarized the results of the PROOF trial in the following manner: “The absence of dose response, a 60 percent dropout rate, and the lack of strong supporting data from BMD [bone mineral density] and markers decrease confidence in the fracture risk data.”

The calcitonin history concluded diplomatically: “after 30 years of clinical experience, calcitonin’s effect on fracture risk is uncertain. As the 40th anniversary of calcitonin’s discovery approaches, perhaps it is time for all interested parties to reassess this drug’s role in treatment of patients with osteoporosis.”[3]

Our conclusion would be more to the point: After 30 years of clinical experience, there is no clear evidence that calcitonin reduces the risk of fracture. In the absence of such evidence, calcitonin should no longer be prescribed for the treatment of patients with osteoporosis.

In July 2012, Health Canada (a regulatory agency similar to the FDA) reported that it is investigating a possible increased risk of cancer with long-term use of calcitonin products. Once the review is complete, recommendations will then be made concerning the use of calcitonin.[4]

In July 2013, Health Canada announced that as of October 1, 2013, calcitonin nasal spray would not be authorized for sale in Canada. After reviewing the available data, the agency concluded that the risk associated with the product is greater than the benefit of using it to treat osteoporosis in post menopausal women.[5]

Also in July 2012, the European Medicines Agency (EMA) issued information concerning the long-term use of calcitonin products and the increased risk of cancer. The EMA stated that these products should be used only for short-term treatment at the lowest effective dose and should not be used for the treatment of osteoporosis. According to the agency, the risk of using calcitonin outweighs its benefit for this indication. In Europe, the product will be available only as an infusion and an injection.[6]

On March 5, 2013, Dr. Sidney Wolfe, then-Director of Public Citizen’s Health Research Group, testified before the FDA’s Reproductive Health Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee. Dr. Wolfe urged the FDA to follow the EMA’s lead and take prompt action to remove nasal calcitonin from the U.S. market.

A brief article in the Medical Letter on Drugs and Therapeutics in April 2013 stated that two advisory committees presented information to the FDA on the risk of cancer in patients using calcitonin. The committees conducted a risk-benefit analysis of the drug and recommended against the use of nasal salmon calcitonin for the treatment of postmenopausal osteoporosis.[7]

In March 2014, the FDA approved revisions to the safety warnings in the professional product labeling for calcitonin-salmon indicating that data from clinical trials revealed an increased risk of cancer in patients treated with calcitonin-salmon compared to patients treated with a placebo.[8]