CLINICAL STUDIES A Randomized Trial of Nasal Spray Salmon Calcitonin in Postmenopausal Women with Established Osteoporosis: the Prevent Recurrence of Osteoporotic Fractures Study Charles H. Chesnut, III, MD, Stuart Silverman, MD, Kim Andriano, PhD, Harry Genant, MD, Alberto Gimona, MD, Steven Harris, MD, Douglas Kiel, MD, Meryl LeBoff, MD, Michael Maricic, MD, Paul Miller, MD, Caje Moniz, MD, Munro Peacock, MD, Peter Richardson, MRCP, Nelson Watts, MD, David Baylink, MD, for the PROOF Study Group PURPOSE: We conducted a 5-year, double-blind, random- ized, placebo-controlled study to determine whether salmon calcitonin nasal spray reduced the risk of new vertebral fractures in postmenopausal women with osteoporosis. SUBJECTS AND METHODS: A total of 1,255 postmeno- pausal women with established osteoporosis were randomly as- signed to receive salmon calcitonin nasal spray (100, 200, or 400 IU) or placebo daily. All participants received elemental cal- cium (1,000 mg) and vitamin D (400 IU) daily. Vertebral frac- tures were assessed with lateral radiographs of the spine. The primary efficacy endpoint was the risk of new vertebral fractures in the salmon calcitonin nasal spray 200-IU group compared with the placebo group. RESULTS: During 5 years, 1,108 participants had at least one follow-up radiograph. A total of 783 women completed 3 years of treatment, and 511 completed 5 years. The 200-IU dose of salmon calcitonin nasal spray significantly reduced the risk of new vertebral fractures by 33% compared with placebo [200 IU: 51 of 287, placebo: 70 of 270, relative risk (RR) = 0.67, 95% confidence interval (CI): 0.47– to 0.97, P = 0.03]. In the 817 women with one to five prevalent vertebral fractures at enroll- ment, the risk was reduced by 36% (RR = 0.64, 95% CI: 0.43– to 0.96, P = 0.03). The reductions in vertebral fractures in the 100-IU (RR = 0.85, 95% CI: 0.60 – to 1.21) and the 400-IU (RR = 0.84, 95% CI: 0.59 – to 1.18) groups were not signifi- cantly different from placebo. Lumbar spine bone mineral den- sity increased significantly from baseline (1% to 1.5%, P 0.01) in all active treatment groups. Bone turnover was inhibited, as shown by suppression of serum type-I collagen cross-linked te- lopeptide (C-telopeptide) by 12% in the 200-IU group (P 0.01) and by 14% in the 400-IU group (P 0.01) as compared with placebo. CONCLUSION: Salmon calcitonin nasal spray at a dose of 200 IU daily significantly reduces the risk of new vertebral fractures in postmenopausal women with osteoporosis. Am J Med. 2000;109:267–276. 2000 by Excerpta Medica, Inc. C alcitonin, a physiologic endogenous inhibitor of bone resorption, decreases osteoclast formation (1,2), osteoclast attachment (2,3), and bone re- sorption in organ culture and animal models (1,4,5). Thus, treatment with calcitonin may be beneficial in dis- eases associated with increased bone resorption, such as postmenopausal osteoporosis (6). Several studies (7–21) have suggested that salmon calcitonin, administered as an injection or a nasal spray, is safe and can stabilize or increase bone mineral density. However, although bone appears to be of normal quality after salmon calcitonin treatment—in terms of mechanical performance, mate- rial density, and patterns of collagen birefringence (22– 26)—the efficacy of salmon calcitonin in reducing frac- tures remains to be determined in a large randomized, controlled trial. Previous studies indicating fracture re- duction at the spine and hip have been retrospective (27) or, if prospective, involved small numbers of participants (13–15,17–20). Therefore, we conducted a 5-year, multi- center clinical trial [the Prevent Recurrence of Osteopo- rotic Fractures (PROOF) study] to determine the long- term efficacy and safety of salmon calcitonin nasal spray in the prevention of vertebral fractures in postmeno- pausal women with osteoporosis. From the University of Washington (CHC), Seattle, Washington; Uni- versity of California, Los Angeles, West Lost Angeles Veterans Affairs Medical Center (SS), Beverly Hills, California; Novartis Pharmaceuti- cals (KA, PR), East Hanover, New Jersey; Departments of Radiology and Medicine (HG), University of California, San Francisco, San Francisco, California; Novartis Pharma AG (AG), Basel, Switzerland; University of California, San Francisco (SH), San Francisco, California; Rhode Island Hospital (DK), Providence, Rhode Island; Brigham and Women’s Hos- pital (ML), Boston, Massachusetts; University of Arizona, Arizona Health Science Center (MM), Tucson, Arizona; Colorado Center for Bone Research (PM), Lakewood, Colorado; King’s College Hospital (CM), London, United Kingdom; Indiana University Medical Center (MP), Indianapolis, Indiana; Emory Clinic (NW), Atlanta, Georgia; Jerry L. Pettis Veterans Hospital (DB), Loma Linda, California. Requests for reprints should be addressed to Charles H. Chesnut, III, MD, University of Washington Medical Center, 1107 NE 45th Street, Suite 440, Seattle, Washington 98105. Manuscript submitted November 8, 1999, and accepted in revised form May 18, 2000. 2000 by Excerpta Medica, Inc. 0002-9343/00/$–see front matter 267 All rights reserved. PII S0002-9343(00)00490-3