Calcitonin (CALCIMAR, MIACALIN) for Osteoporosis - Value Uncertain After 30 Years

Physicians and pharmacists from the Food and Drug Administration (FDA), in the March 19, 2002, issue of the medical journal The Lancet reviewed the regulatory history of calcitonin (CALCIMAR, MIACALCIN) in the treatment of postmenopausal osteoporosis. Over six years ago, in the December 1995 issue of Worst Pills, Best Pills News, we listed calcitonin nasal spray as a Do Not Use drug because there was no credible evidence that the drug reduced the risk of fractures in postmenopausal women with osteoporosis.

Calcitonin nasal spray is now marketed by Novartis Pharmaceuticals Corporation based in East Hanover, New Jersey.

This history provides a rare insight into drug regulation at the FDA by agency scientists. This type of analysis of the drug approval process has not been seen since the mid-1980s when Congress stopped holding meaningful oversight hearings into FDA operations.

Keep the following facts in mind as you read the calcitonin history:

1. 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 (PREMARIN) are no longer approved for the treatment of postmenopausal osteoporosis.

2. Approximately 3.5 million prescriptions for calcitonin nasal spray were dispensed in 2002 at a retail cost of almost $300 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 (CALCIMAR) 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.

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 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 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 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 underway. 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 in the average number of vertebral fractures at the beginning of the study between the calcitonin and control groups. 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 underway by Novartis. The company sponsored a large clinical trial known as the Prevent Reoccurrence of Osteoporotic Fractures, or PROOF trial. This 5-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 published in late 2000.

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 FDA staffers who prepared the recently published calcitonin history concluded diplomatically that:

...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.

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. First, physicians in their everyday medical practice cannot differentiate between a useful drug and one that only leads to increased cost without added benefit to patients. This is the case with calcitonin. It continues to be prescribed, causing economic harm to patients, despite the fact that there is no clear evidence that the drug provides them a meaningful benefit in terms of fracture risk. A second lesson is that when the FDA raises the bar for new drug approvals patients get better drugs. Requiring documentation of the efficacy of a drug in reducing fractures before being approved for the treatment of osteoporosis brought drugs that reduced fracture risk. Though this reduction in risk is very small with the new drugs, it is a large improvement over calcitonin. Unfortunately, the treatment of osteoporosis is one of the few areas where the FDA has raised the bar. Most drugs are still approved — with only the hope — not the proof that they will provide a meaningful outcome for patients.

What You Can Do

We will leave you with the same advice we provided in December 1995 when we listed calcitonin nasal spray as Do Not Use.

Before you decide to use a drug to prevent or treat osteoporosis discuss with your doctor the risks and benefits of drug treatment.

Not all postmenopausal women will develop osteoporosis. Women who are thin or small-boned, particularly Asian or white women, and those who drink more than two alcoholic drinks per day are at elevated risk of osteoporosis. Black women, heavy, large-boned women, and women who get a lot of exercise have a lower risk.

You can take steps to prevent osteoporosis. These include getting a lot of calcium (1200-1500 mg per day) in your diet beginning in early adulthood and regularly doing weight-bearing exercises such as jogging, walking, playing tennis, bicycling, and strength training. These steps are enough to prevent osteoporosis in many adults.