A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis:​ the prevent recurrence of osteoporotic fractures study

Chesnut, Charles H.<sup>1</sup>; Silverman, Stuart<sup>2</sup>; Andriano, Kim<sup>3</sup>; Genant, Harry<sup>4</sup>; Gimona, Alberto<sup>5</sup>; Harris, Steven<sup>6</sup>; Kiel, Douglas<sup>7</sup>; LeBoff, Meryl<sup>8</sup>; Maricic, Michael<sup>9</sup>; Miller, Paul<sup>10</sup>; Moniz, Caje<sup>11</sup>; Peacock, Munro<sup>12</sup>; Richardson, Peter<sup>3</sup>; Watts, Nelson<sup>13</sup>; Baylink, David<sup>14</sup>

Affiliations

¹University of Washington, Seattle, Washington

²University of California, Los Angeles, West Lost Angeles Veterans Affairs, Beverly Hills, California Medical Center

³Novartis Pharmaceuticals, East Hanover, New Jersey

⁴Departments of Radiology and Medicine, University of California, San Francisco, San Francisco, California

⁵Novartis Pharma AG, Basel, Switzerland

⁶University of California, San Francisco, San Francisco, California

⁷Rhode Island Hospital, Providence, Rhode Island

⁸Brigham and Women’s Hospital, Boston, Massachusetts

⁹University of Arizona, Arizona Health Science Center, Tucson, Arizona

¹⁰Colorado Center for Bone Research, Lakewood, Colorado

¹¹King’s College Hospital, London, United Kingdom

¹²Indiana University Medical Center, Indianapolis, Indiana

¹³Emory Clinic, Atlanta, Georgia

¹⁴Jerry L. Pettis Veterans Hospital, Loma Linda, California

Abstract

Purpose: We conducted a 5-year, double-blind, randomized, 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 postmenopausal women with established osteoporosis were randomly assigned to receive salmon calcitonin nasal spray (100, 200, or 400 IU) or placebo daily. All participants received elemental calcium (1,000 mg) and vitamin D (400 IU) daily. Vertebral fractures 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 enrollment, 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 significantly different from placebo. Lumbar spine bone mineral density 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 telopeptide (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.

Links

DOI: 10.1016/S0002-9343(00)00490-3

PubMed: 10996576

WoS: 000089356600001

History

Received: 1999-11-8

Accepted: 2000-05-18

Cited Works (7)

Year	Entry
1996	Riggs BL, Melton LJ III, O'Fallon WM. Drug therapy for vertebral fractures in osteoporosis: evidence that decreases in bone turnover and increases in bone mass both determine antifracture efficacy. Bone. March 1996;18(3)(suppl 1):197S-201S.
1996	Garnero P, Hausherr E, Chapuy M, Marcelli C, Grandjean H, Muller C, Cormier C, Bréart G, Meunier PJ, Delmas PD. Markers of bone resorption predict hip fracture in elderly women: the EPIDOS prospective study. J Bone Miner Res. October 1996;11(10):1531-1538.
1997	Cooper C. The crippling consequences of fractures and their impact on quality of life. Am J Med. August 18, 1997;103(2)(suppl 1):S12-S19.
1997	Chavassieux PM, Arlot ME, Reda C, Wei L, Yates AJ, Meunier PJ. Histomorphometric assessment of the long-term effects of alendronate on bone quality and remodeling in patients with osteoporosis. J Clin Invest. September 15, 1997;100(6):1475-1480.
1996	Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, Bauer DC, Genant HK, Haskell WL, Marcus R, Ott SM, Torner JC, Quandt SA, Reiss TF, Ensrud KE. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet. December 7, 1996;348(9041):1535-1541.
1996	Genant HK, Jergas M, Palermo L, Nevitt M, Valentin RS, Black D, Cummings SR; The Study of Osteoporotic Fractures Research Group. Comparison of semiquantitative visual and quantitative morphometric assessment of prevalent and incident vertebral fractures in osteoporosis. J Bone Miner Res. July 1996;11(7):984-996.
1995	Liberman UA, Weiss SR, Bröll J, Minne HW, Quan H, Bell NH, Rodriguez-Portales J, Downs RW Jr, Dequeker J, Favus M, Seeman E, Recker RR, Capizzi T, Santora AC, Lombardi A, Shah RV, Hirsch LJ, Karpf DB; Group, Alendronate Phase III Osteoporosis Treatment Study. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. NEJM. November 30, 1995;333(22):1437-1443.

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Year	Entry
2002	Wehrli F, Saha P, Gomberg B, Song H, Snyder P, Benito M, Wright A, Weening R. Role of magnetic resonance for assessing structure and function of trabecular bone. Top Magn Reson Imaging. October 2002;13(5):335-355.
2002	Cummings SR, Karpf DB, Harris F, Genant HK, Ensrud K, LaCroix AZ, Black DM. Improvement in spine bone density and reduction in risk of vertebral fractures during treatment with antiresorptive drugs. Am J Med. March 2002;112(4):281-289.
2004	Siris ES, Chen Y-T, Abbott TA, Barrett-Connor E, Miller PD, Wehren LE, Berger ML. Bone mineral density thresholds for pharmacological intervention to prevent fractures. Arch Intern Med. May 24, 2004;164(10):1108-1112.
2006	Allen MR, Iwata K, Sato M, Burr DB. Raloxifene enhances vertebral mechanical properties independent of bone density. Bone. November 2006;39(5):1130-1135.
2020	Watts NB, Chesnut CH III, Genant HK, Harris ST, Jackson RD, Licata AA, Miller PD, Mysiw WJ, Richmond B, Valent D. History of etidronate. Bone. May 2020;134:115222.
2023	Surowiec RK, Saldivar R, Rai RK, Metzger CE, Jacobson AM, Allen MR, Wallace JM. Ex vivo exposure to calcitonin or raloxifene improves mechanical properties of diseased bone through non-cell mediated mechanisms. Bone. August 2023;173:116805.
2005	Felsenberg D, Boonen S. The bone quality framework: determinants of bone strength and their interrelationships, and implications for osteoporosis management. Clin Ther. January 2005;27(1):1-11.
2016	Camacho PM, Petak SM, Binkley N, Clarke BL, Harris ST, Hurley DL, Kleerekoper M, Lewiecki EM, Miller PD, Narula HS, Pessah-Pollack R, Tangpricha V, Wimalawansa SJ, Watts NB. American Association of Clinical Endocrinologists and American College of Endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis — 2016. Endocr Pract. September 1, 2016;22(suppl 4):1-42.
2020	Camacho PM, Petak SM, Binkley N, Diab DL, Eldeiry LS, Farooki A, Harris ST, Hurley DL, Kelly J, Lewiecki EM, Pessah-Pollack R, McClung M, Wimalawansa SJ, Watts NB. American Association of Clinical Endocrinologists/American College of Endocrinology Clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis: 2020 update. Endocr Pract. May 2020;26(suppl 1):1-46.
2002	Cranney A, Guyatt G, Griffith L, Wells G, Tugwell P, Rosen C; The Osteoporosis Methodology Group; The Osteoporosis Research Advisory Group. Meta-analyses of therapies for postmenopausal osteoporosis, IX: summary of meta-analyses of therapies for postmenopausal osteoporosis. Endocr Rev. August 2002;23(4):570-578.
2002	Cummings SR, Bates D, Black DM. Clinical use of bone densitometry: scientific review. JAMA. October 16, 2002;288(15):1889-1897.
2002	Riggs BL, Melton LJ III. Bone turnover matters: the raloxifene treatment paradox of dramatic decreases in vertebral fractures without commensurate increases in bone density. J Bone Miner Res. January 2002;17(1):11-14.
2005	Riggs BL, Parfitt AM. Drugs used to treat osteoporosis: the critical need for a uniform nomenclature based on their action on bone remodeling. J Bone Miner Res. February 2005;20(2):177-184.
2019	Bouxsein ML, Eastell R, Lui L-Y, Wu LA, de Papp AE, Grauer A, Marin F, Cauley JA, Bauer DC, Black DM; FNIH Bone Quality Project. Change in bone density and reduction in fracture risk: a meta-regression of published trials. J Bone Miner Res. April 2019;34(4):632-642.
2022	Eastell R, Vittinghoff E, Lui L-Y, McCulloch CE, Pavo I, Chines A, Khosla S, Cauley JA, Mitlak B, Bauer DC, Bouxsein M, Black DM. Validation of the surrogate threshold effect for change in bone mineral density as a surrogate endpoint for fracture outcomes: the FNIH-ASBMR SABRE project. J Bone Miner Res. January 2022;37(1):29-35.
2002	Hochberg MC, Greenspan S, Wasnich RD, Miller P, Thompson DE, Ross PD. Changes in bone density and turnover explain the reductions in incidence of nonvertebral fractures that occur during treatment with antiresorptive agents. J Clin Endocrinol Metab. April 2002;87(4):1586-1592.
2019	Eastell R, Rosen CJ, Black DM, Cheung AM, Murad MH, Shoback D. Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. May 2019;104(5):1595-1622.
2002	Delmas PD. Treatment of postmenopausal osteoporosis. Lancet. June 8, 2002;359(9322):2018-2026.
2006	Sambrook P, Cooper C. Osteoporosis. Lancet. June 17, 2006;367(9527):2010-2018.
2017	Khosla S, Hofbauer LC. Osteoporosis treatment: recent developments and ongoing challenges. Lancet Diabetes Endocrinol. November 2017;5(11):898-907.
2001	Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster J-Y, Hodsman AB, Eriksen EF, Ish-Shalom S, Genant HK, Wang O, Mellström D, Oefjord ES, Marcinowska-Suchowierska E, Salmi J, Mulder H, Halse J, Sawicki AZ, Mitlak BH. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. NEJM. May 10, 2001;344(19):1434-1441.
2007	Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, Leung PC, Man Z, Mautalen C, Mesenbrink P, Hu H, Caminis J, Tong K, Rosario-Jansen T, Krasnow J, Hue TF, Sellmeyer D, Eriksen EF, Cummings SR; HORIZON Pivotal Fracture Trial. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. NEJM. May 3, 2007;356(18):1809-1822.
2008	Kanis JA, Burlet N, Cooper C, Delmas PD, Reginster J-Y, Borgstrom F, Rizzoli R; European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO). European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int. April 2008;19(4):399-428.
2011	Vasikaran S, Eastell R, Bruyère O, Foldes AJ, Garnero P, Griesmacher A, McClung M, Morris HA, Silverman S, Trenti T, Wahl DA, Cooper C, Kanis JA; OF-IFCC Bone Marker Standards Working Group. Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards. Osteoporos Int. February 2011;22(2):391-420.
2013	Kanis JA, McCloskey EV, Johansson H, Cooper C, Rizzoli R, Reginster J-Y; Scientific Advisory Board of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO); Committee of Scientific Advisors of the International Osteoporosis Foundation (IOF). European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int. January 2013;24(1):23-57.
2014	Cosman F, de Beur SJ, LeBoff MS, Lewiecki EM, Tanner B, Randall S, Lindsay R. Clinician’s guide to prevention and treatment of osteoporosis. Osteoporos Int. October 2014;25(10):2359-2381.
2007	Schneider P. Ultrastructural Phenotyping of Murine Bone Using Synchrotron Micro- and Nano-Computed Tomography [PhD thesis]. Swiss Federal Institute of Technology Zürich; 2007.
2018	George JK. Using Finite Element Models Under Multiple Loading Conditions to Improve the Association Between Radius and Tibia Microarchitecture and Prevalent Osteoporotic Vertebral Fracture [Master's thesis]. Calgary, AB: University of Calgary; May 2018.
2018	Oweis R. Associations Between Fluoride Intakes, Bone Outcomes and Dental Fluorosis [PhD thesis]. University of Iowa; May 2018.