WHITE OAK, MD 29 Mar 2013—The benefits of calcitonin-salmon for the treatment of postmenopausal osteoporosis are minimal and do not outweigh an uncertain cancer risk associated with the drug, a slim majority of FDA advisers concluded March 5.
The 12–9 vote by members of FDA's Drug Safety and Risk Management Advisory Committee and the Advisory Committee for Reproductive Health Drugs was in line with a decision reached last July by European regulators.
In Europe, because of the possible cancer risk, calcitonin-containing products may be used only as short-term treatment for hypercalcemia or for the prevention of acute bone loss due to sudden immobilization or Paget's disease.
Data suggesting calcitonin may cause cancer came from clinical trials of an investigational oral formulation of the drug being developed by Denmark-based Nordic Bioscience for the treatment of osteoarthritis. In those studies, a possible link between calcitonin use and prostate cancer was noted by a safety monitoring committee.
After examining the study data, FDA stated that the initial risk of prostate cancer appeared equal among calcitonin-treated patients and placebo recipients, and the perceived safety signal was "not of great concern."
FDA and Novartis, which markets the Miacalcin line of calcitonin-salmon products, subsequently conducted a meta-analysis of all malignancies reported in published studies of the drug. Skin and breast cancers constituted the majority of malignancies observed, but many other cancer types were also reported.
Paul Aftring, global program head for Novartis, cautioned that the trials weren't designed to capture cancer data systematically or link incidents of cancer to the administration of the drug, and patients weren't screened at baseline for some of the cancers that were eventually detected.
And the variety of cancer types further complicated the effort to find a causal relationship between administration of the drug and a cancer diagnosis.
"There are no consistencies with regard to tissue type, organ type," he said, nor was there a dose–response relationship between calcitonin and a finding of malignancy.
Nevertheless, both FDA and Novartis found that cancers were more common in calcitonin-treated patients than in those given a placebo.
FDA Medical Officer Theresa Kehoe said that because of limitations in the data, "we cannot assess the strength of the potential cancer signal with the data at hand—but it does appear plausible."
FDA did not ask the advisers to vote on specific changes to the labeling of calcitonin-salmon products.
According to FDA, calcitonin-salmon, a synthetic hormone, was initially approved in 1975 for the treatment of Paget's disease of the bone. An indication for the treatment of postmenopausal osteoporosis was added to the labeling in 1984.
Kehoe said an estimated 8 million women in the United States have osteoporosis. The condition increases the risk of fractures, with the most common types affecting the spine, hip, or forearm.
The postmenopausal osteoporosis indication for calcitonin-salmon was based on data showing that the drug increases total body calcium levels and improves bone mineral density. At the time, Kehoe said, those were considered acceptable surrogate endpoints for fracture prevention.
But that's not the case today.
Of the five classes of FDA-approved drugs indicated for the treatment of postmenopausal osteoporosis, calcitonin products are the only ones for which fracture prevention data were not required for marketing approval. FDA began requiring such data in 1994 for a postmenopausal osteoporosis indication, according to the agency.
Kehoe said just one postmarketing study has been conducted to examine whether calcitonin-salmon prevents fractures. But only half of the expected 300 patients enrolled in the study, and half of them dropped out before the three-year endpoint. Problems with patient randomization and other issues affected the usefulness of the limited data gleaned from the study.
Kehoe said an FDA advisory committee in 1991 concluded that no conclusions could be made about the fracture data from the study.
Advisory committee member T. Mark Woods, clinical coordinator for pharmacy at St. Luke's Hospital in Kansas City, Missouri, voted with the majority to exclude the use of calcitonin-salmon in postmenopausal women.
"I really didn't believe that there was sufficient efficacy data to support [this use], especially in view of the new data regarding the potential carcinogenic risk," Woods said.
Woods said calcitonin-salmon is on the formulary at St. Luke's but is used very infrequently—mostly for the treatment of Paget's disease or for patients with painful compression fractures who cannot use other agents.
Woods encouraged pharmacists in outpatient settings to be familiar with osteoporosis. He said the profession has a role in helping to identify patients who are at risk for the disease and ensuring that they receive appropriate drug therapy and vitamin D and calcium supplementation.