For personal use. Only reproduce with permission from The Lancet Publishing Group. mean number of vertebral fractures at baseline between the Calcimar and control groups. 9 The results from this study were ultimately judged unreliable, and calcitonin’s efficacy in reducing fracture remained unknown. After the failed fracture study, the company cited competition for patients and investigators, noncompliance with daily injections, and the questionable ethics of giving some patients placebo for 3 years, as reasons against attempting a second fracture study. 9 Use of Calcimar has since declined. However, calcitonin lived on in a formulation more amenable to patient compliance. By the early 1990s, a nasally administered calcitonin (Miacalcin nasal spray, Novartis, East Hannock, NJ, USA) was in the late stages of development—under the stewardship of a different company. In fact, a large, randomised, double-blind 5-year study comparing the effects of 100 IU, 200 IU, and 400 IU of Miacalcin nasal spray daily with placebo on incidence of vertebral fractures was underway. The study was known as the Prevent Reoccurrence of Osteoporotic Fractures, or PROOF trial. 9 In 1994, another FDA advisory committee convened to discuss results from studies of Miacalcin nasal spray. 9 By this time, measurement of bone mineral density with dual photon X-ray absorptiometry was widely available. Increases in bone mineral density, as measured by dual photon X-ray absorptiometry, were deemed by many to be a reasonable surrogate for reduced risk of osteoporotic fracture. Data from five randomised, placebo-controlled trials lasting 1–2 years and including about 550 patients were presented to the committee. The company concluded, and the committee agreed, that the drug significantly increased bone mineral density of the lumbar spine compared with placebo. Because of the favourable fracture trends from the bone mineral density studies and of the fact that the PROOF trial was continuing, the advisory committee concluded that the potential benefits of Miacalcin nasal spray outweighed the potential risks and recommended its approval. The FDA subsequently approved Miacalcin nasal spray for treatment of postmenopausal osteoporosis in women who were more than 5 years postmenopausal. 10 The drug’s label explicitly stated that “the evidence of efficacy [was] based on increases in spinal bone mineral density”, not fracture data.

While physicians and patients waited for definitive evidence of calcitonin’s efficacy in reduction of risk of fractures, reports from small studies began to be published. Although at least one study reported an increased risk of fracture in patients receiving calcitonin, others claimed beneficial effects. 11–15 Then, after 20 years of waiting for conclusive evidence that calcitonin reduces risk of fracture, the results of the PROOF trial were published in late 2000. 16