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Odanacatib for the treatment of postmenopausal osteoporosis : Results of the LOFT multicentre, randomised, double-blind, placebo-controlled trial and LOFT Extension study

McClung, Michael R.
; 
O'Donoghue, Michelle L.
; 
Papapoulos, Socrates E.
; 
Bone, Henry
; 
Langdahl, Bente
; 
Saag, Kenneth G.
; 
Reid, Ian R.
; 
Kiel, Douglas P.
; 
Cavallari, Ilaria
; 
Bonaca, Marc P.
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McClung, Michael R.
O'Donoghue, Michelle L.
Papapoulos, Socrates E.
Bone, Henry
Langdahl, Bente
Saag, Kenneth G.
Reid, Ian R.
Kiel, Douglas P.
Cavallari, Ilaria
Bonaca, Marc P.
Wiviott, Stephen D.
de Villiers, Tobias
Ling, Xu
Lippuner, Kurt
Nakamura, Toshitaka
Reginster, Jean-Yves
Rodriguez-Portales, Jose Adolfo
Roux, Christian
Zanchetta, José
Zerbini, Cristiano A. F.
Park, Jeong-Gun
Im, KyungAh
Cange, Abby
Grip, Laura T.
Heyden, Norman
DaSilva, Carolyn
Cohn, Dosinda
Massaad, Rachid
Scott, Boyd B.
Verbruggen, Nadia
Gurner, Deborah
Miller, Deborah L.
Blair, Micki L.
Polis, Adam B.
Stoch, S. Aubrey
Santora, Arthur
Lombardi, Antonio
Leung, Albert T.
Kaufman, Keith D.
Sabatine, Marc S.
Mautalén, Carlos Alfredo
Man, Zulema
Zanchetta, Jose Ruben
Magaril, Clelia Haydee
Sambrook, Philip
Reginster, Jean-Yves
Geusens, Piet
Goemaere, Stefan
Albergaria, Ben Hur
Zerbini, Cristiano Augusto de Freitas
Castro, Marise Lazaretti
Gregorio, Luiz Henrique
Stoilov, Rumen
Borissova, Anna-Maria I.
Hristozov, Kiril Hristov
Temelkova, Nataliya L.
Daskalova, Ivona Kirilova
Kuzmanova, Stefka Ivanova
Yaneva-Bichovska, Daniela
Batalov, Anastas Zgurov
Riedemann, Pablo
Rodriguez Portales, José Adolfo
Tang, Hai
Zhu, hanmin
Zhang, Zhenlin
Chao, Aijun
Hu, Yali
Liu, Zhiming
Lu, Juming
Qiu, Mingcai
Gao, Xin
Zhang, Shaofen
Xu, Ling
Xia, Weibo
Liao, Eryuan
Yang, Wenying
Wu, Wen
Dai, Kerong
Hu, Renming
Tang, Hai
Jaller, Juan Jose
Cabal, Francisco
Molina, José Fernando
Cure Cure, Carlos A.
Yupanqui-Lozno, Hernan
Chalem, Philippe
Londono, John
Abello, Mauricio
Tobias, Edgardo D.
Otero, William
Nikolic, Tatjana
Miskic, Blazenka
Stepan, Jan
Vyskocil, Vaclav
Novosad, Libor
Slesinger, Jan
Novosad, Pavel
Vlckova, Erika
Bortlik, Ladislav
Dokoupilova, Eva
Hala, Tomas
Jensen, Jens-Erik Beck
Brixen, Kim Torsten
Langdahl, Bente Lomholt
Schwarz, Peter
Eskildsen, Peter Claes
Eiken, Pia Agnete
Hermann, Anne Pernille
Gram, Jeppe
Schou, Maiken Brix
Alexandersen, Peter
Nedergaard, Bettina
Mejía, Dolores Magdalena
Estrella De Henriquez, Lourdes
Páez, Norka
Velazco, Casimiro
Valter, Ivo
Vahula, Kadri-Liina
Kull, Ingrid
Maasalu, Katre
Chapurlat, Roland
Fardellone, Patrice
Benhamou, Claude Laurent
Roux, Christian
Weryha, Georges
Herkt, Volkmar
Martz, Rene
Nischik, Ruth
Spieler, Wolfgang
Contzen, Christel
Felsenberg, Dieter
Frieling, Isolde
Frahm, Eike
Briones, Henry
Sandoval, Boris
Barrios, Patricia
García, Abraham
Avendaño, Carlos
González, Magdalena
Guerra, Jeremías
Tuna, Maria
Díaz, Olga Marina
Samayoa, Eduardo
López, Edgar
Barrera, José Raúl
Palencia, Mainor
Cifuentes, Mayra
Alvarado, Georgina
López, Miriam
Chavez, Nilmo
Haase, Franklin
Rivera, Ruddy
González, Claudio
Tan, Kathryn
Leung, Ping Chung
Mandalam, Sheshadri
Pitale, Shailesh Umakant
Bantwal, Ganapathi
Ammini, Ariachery Chinamma
Shaikh, Shehla Sajid Akhta
Kanakatte Mylariah, Prasanna Kumar
Dharmalingam, Mala
Mukhopadhyay, Satinath
Jain, Arpit
Singh, Parminder
Shetty, Naresh
Sathyanarayana, Srikanta Shamanna
Shah, Nalini
Chadha, Manoj Dharam
Bhandankar, Rajendra
Velayutham, Kumaravel
Marwah, Sudha
John, Mathew
Sahay, Rakesh Kumar
Adami, Silvano
Nuti, Ranuccio
Bianchi, Gerolamo
Brandi, Maria Luisa
Minisola, Salvatore
Fiore, Carmelo Erio
Rubinacci, Alessandro
Miyajima, Hisayuki
Yamane, Hiroo
Nakatani, Yuji
Okamoto, Sumiaki
Kuroda, Koji
Fujimori, Motoaki
Itabashi, Akira
Katayama, Kuniaki
Nakajo, Satoru
Somekawa, Yoshiaki
Ohsawa, Yoshimitsu
Tajima, Wataru
Mizuno, Katsunori
Mori, Shigeru
Kanabuchi, Takato
Hashizume, Hiroyuki
Oka, Nobuyuki
Hamada, Kazutoshi
Yamaguchi, Motoi
Hirahara, Fumiki
Atobe, Masaaki
Ohtake, Yoshiharu
Ichikawa, Shuichi
Onishi, Tomoyuki
Matsumoto, Kou
Nakamura, Tetsuro
Shirasawa, Eishi
Katayama, Ko
Takahashi, Mitsugu
Oguma, Tadanori
Matsui, Hideo
Katoh, Yoshiharu
Shigenobu, Keiichi
Onishi, Tsutomu
Shibukawa, Masato
Ikeda, Satoshi
Osaka, Kazuhiro
Kanda, Ryosuke
Inobe, Yoshito
Shigenobu, Masaharu
Hasegawa, Morimasa
Yamaji, Tetsuo
Miyazaki, Yu
Ito, Takayasu
Nakamura, Eisuke
Nagai, Shinji
Lim, Sung-Kil
Chung, Yoon-Sok
Shin, Chan-Soo
Min, Yong-Ki
Kim, Ghi Su
Yoon, Hyun Koo
Kang, Moo-Il
Yang, Kyu-Hyun
Park, Hyoung Moo
Kim, In Joo
Chung, Dong Jin
Chung, Ho Yeon
Jaundzeikare, Sandra
Andersone, Dace
Medne, Agita
Yaghi, Yasser
Alekna, Vidmantas
Kasiulevicius, Vytautas
Purtokaite - Labutiniene, Irina
Krasauskiene, Aurelija
Varanaviciene, Jurate
Basijokiene, Vida
Abraitiene, Agne
Radzeviciene, Lina
Walliser, Jesus
García Hernández, Pedro Alberto
Araujo, Maria Frida
Avila Armengol, Hilario Ernesto
De la Peña, Pilar
Tamayo, Juan
Zazueta, Beatriz
Cons, Fidencio
Gilchrist, Nigel Leslie
Reid, Ian Reginald
Leikis, Robert
Jones, Peter
Singh, Joe Gragrath Pradeep
Halse, Johan Inge
Syversen, Unni
Høivik, Hans Olav
Øfjord, Erik Snorre
Gulseth, Hans Christian
Elle, Sigbjørn
Norheim, Paal Dag
Calvo Quiroz, Armando A.
Cesar Augusto, Pastor A.
León Portocarrero, Manuel Gustavo
Vidal Neira, Luis Fernando
Chavez, Jose
Garro Barrera, Boris
Kuroiwa Sampei, Rita
Luis Fernando, Bellatín V.
Oquelis Cabredo, Rogger
Castillo, Sonia
Morales, Agustin Miguel G.
Tan, Perry Pua
Leagogo, Liberato Antonio C.
Wang, Edward H. M.
Li-Yu, Julie T.
Sawicki, Andrzej Z.
Stasiuk, Barbara
Kania, Grzegorz
Lorenc, Roman
Sidorowicz-Bialynicka, Anna
Szczepanski, Leszek
Franek, Edward
Filip, Rafal
Sekula, Jan
Blicharski, Tomasz
Leszczynski, Piotr
Sewerynek, Ewa
Miazgowski, Tomasz
Milewicz, Andrzej
Dabrowska, Magda
Romaszko, Jerzy
Pluskiewicz, Wojciech
Wojnowski, Lukasz
Codreanu, Catalin
Bolosiu, Horatiu
Ionescu, Ruxandra
Zosin, Ioana
Macovei, Liviu
Bojinca, Mihai
Radulescu, Florin
Pop, Simona
Sarbu, Adrian
Benevolenskaya, Lidia I.
Nasonov, Evgeny L.
Rozhinskaya, Lyudmila Ya
Oganov, Raphael G.
Rodionova, Svetlana S.
Shlyakhto, Eugeny Vladimirovich
Trofimov, Vasiliy
Zotkin, Eugeny G.
Zazerskaya, Irina E.
Grineva, Elena N.
Ershova, Olga
Lesnyak, Olga
Ostroumova, Olga D.
Malichenko, Svetlana B.
Pikhlak, Eduard G.
Pilyaev, Valery G.
Raskina, Tatiana
Zonova, Elena V.
Shirinsky, Valery S.
Dimic, Aleksandar N.
Cobeljic, Goran
Vujovic, Svetlana
Ellis, Graham Charlston
Lipschitz, Stanley
De Villiers, Tobias Johannes
De Weerd, Albert Jan
Vally, Tasneem
Trinder, Yvonne
Coetsee, Jacobus Ludewikus
Davis, Charles Pierre
Nayiager, Savithree
Hough, Frans Stephanus
Oelofse, Louis F.
van der Walt, Eugene
Lombaard, Johannes Jurgens
Blignaut, Suzanne
Govind, Uttam
Fouche, Leon Frederik
Kruger, Dawid Stephanus
Dalmeyer, Johannes Paul
Ferreira, Mada M.
Escudero-Contreras, Alejandro
Muñoz Torres, Manuel
Hawkins Carranza, Federico
Perez Castrillon, Jose Luis
García Meijide, Juan Antonio
Jodar Gimeno, Esteban
Palacios Gil-Antuñana, Santiago
de Teresa Parreno, Luis
Martín Mola, Emilio
Alvarez Sanchez, Carmen
Lippuner, Kurt
Tsai, Keh-Sung
Tu, Shih-Te
Chen, Jung-Fu
Lee, Oscar Kuang-Sheng
Hsu, Wen-Wei
Grygorieva, Natalia Viktorivna
Povoroznyuk, Vladyslav Volodymyrovych
Korzh, Mykola Oleksiiovych
Loskutov, Oleksandr Levgeniiovych
Chukov, Andriy Borysovych
Sarmiento, Rex
Thomas, Hawys
Donnachie, Hugh
Pavel-Knox, Irina
Shaw, Hilary
Hassanin, Hana
Abdulhakim, Essam Eldin Ahmed
Savani, Naren
Bachmann, Gloria A.
Barrett-Connor, Elizabeth
Binkley, Neil C.
Bone, Henry G.
Brandon, Donald M.
Checketts, Darin David
Fraser, Neil J.
Watts, Nelson B.
Geller, Steven A.
Gimbel, Joseph S.
Greenwald, Maria White
Holt, Peter A.
Johnston, Cyrus Conrad
Fang, Chien
Kiel, Douglas P.
Klashman, David J.
Lewiecki, E. Michael
Lowenstein, Mitchell B.
McClung, Michael Roy
Nattrass, Susan M.
Odio, Alberto
Levengood, Julie
Romaguera, Josefina
Saag, Kenneth G.
Sebai, Mohamed Bassam
Snyder, Brian
Kutner, Mark Eliot
Streja, Dan
Schwartz, Elliott P.
Christiansen, Mark G.
Abstract
Background Odanacatib, a cathepsin K inhibitor, reduces bone resorption while maintaining bone formation. Previous work has shown that odanacatib increases bone mineral density in postmenopausal women with low bone mass. We aimed to investigate the efficacy and safety of odanacatib to reduce fracture risk in postmenopausal women with osteoporosis. Methods The Long-term Odanacatib Fracture Trial (LOFT) was a multicentre, randomised, double-blind, placebo-controlled, event-driven study at 388 outpatient clinics in 40 countries. Eligible participants were women aged at least 65 years who were postmenopausal for 5 years or more, with a femoral neck or total hip bone mineral density T-score between −2·5 and −4·0 if no previous radiographic vertebral fracture, or between −1·5 and −4·0 with a previous vertebral fracture. Women with a previous hip fracture, more than one vertebral fracture, or a T-score of less than −4·0 at the total hip or femoral neck were not eligible unless they were unable or unwilling to use approved osteoporosis treatment. Participants were randomly assigned (1:1) to either oral odanacatib (50 mg once per week) or matching placebo. Randomisation was done using an interactive voice recognition system after stratification for previous radiographic vertebral fracture, and treatment was masked to study participants, investigators and their staff, and sponsor personnel. If the study completed before 5 years of double-blind treatment, consenting participants could enrol in a double-blind extension study (LOFT Extension), continuing their original treatment assignment for up to 5 years from randomisation. Primary endpoints were incidence of vertebral fractures as assessed using radiographs collected at baseline, 6 and 12 months, yearly, and at final study visit in participants for whom evaluable radiograph images were available at baseline and at least one other timepoint, and hip and non-vertebral fractures adjudicated as being a result of osteoporosis as assessed by clinical history and radiograph. Safety was assessed in participants who received at least one dose of study drug. The adjudicated cardiovascular safety endpoints were a composite of cardiovascular death, myocardial infarction, or stroke, and new-onset atrial fibrillation or flutter. Individual cardiovascular endpoints and death were also assessed. LOFT and LOFT Extension are registered with ClinicalTrials.gov (number NCT00529373) and the European Clinical Trials Database (EudraCT number 2007-002693-66). Findings Between Sept 14, 2007, and Nov 17, 2009, we randomly assigned 16 071 evaluable patients to treatment: 8043 to odanacatib and 8028 to placebo. After a median follow-up of 36·5 months (IQR 34·43–40·15) 4297 women assigned to odanacatib and 3960 assigned to placebo enrolled in LOFT Extension (total median follow-up 47·6 months, IQR 35·45–60·06). In LOFT, cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 3·7% (251/6770) versus 7·8% (542/6910), hazard ratio (HR) 0·46, 95% CI 0·40–0·53; hip fractures 0·8% (65/8043) versus 1·6% (125/8028), 0·53, 0·39–0·71; non-vertebral fractures 5·1% (412/8043) versus 6·7% (541/8028), 0·77, 0·68–0·87; all p<0·0001. Combined results from LOFT plus LOFT Extension for cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 4·9% (341/6909) versus 9·6% (675/7011), HR 0·48, 95% CI 0·42–0·55; hip fractures 1·1% (86/8043) versus 2·0% (162/8028), 0·52, 0·40–0·67; non-vertebral fractures 6·4% (512/8043) versus 8·4% (675/8028), 0·74, 0·66–0·83; all p<0·0001. In LOFT, the composite cardiovascular endpoint of cardiovascular death, myocardial infarction, or stroke occurred in 273 (3·4%) of 8043 patients in the odanacatib group versus 245 (3·1%) of 8028 in the placebo group (HR 1·12, 95% CI 0·95–1·34; p=0·18). New-onset atrial fibrillation or flutter occurred in 112 (1·4%) of 8043 patients in the odanacatib group versus 96 (1·2%) of 8028 in the placebo group (HR 1·18, 0·90–1·55; p=0·24). Odanacatib was associated with an increased risk of stroke (1·7% [136/8043] vs 1·3% [104/8028], HR 1·32, 1·02–1·70; p=0·034), but not myocardial infarction (0·7% [60/8043] vs 0·9% [74/8028], HR 0·82, 0·58–1·15; p=0·26). The HR for all-cause mortality was 1·13 (5·0% [401/8043] vs 4·4% [356/8028], 0·98–1·30; p=0·10). When data from LOFT Extension were included, the composite of cardiovascular death, myocardial infarction, or stroke occurred in significantly more patients in the odanacatib group than in the placebo group (401 [5·0%] of 8043 vs 343 [4·3%] of 8028, HR 1·17, 1·02–1·36; p=0·029, as did stroke (2·3% [187/8043] vs 1·7% [137/8028], HR 1·37, 1·10–1·71; p=0·0051). Interpretation Odanacatib reduced the risk of fracture, but was associated with an increased risk of cardiovascular events, specifically stroke, in postmenopausal women with osteoporosis. Based on the overall balance between benefit and risk, the study's sponsor decided that they would no longer pursue development of odanacatib for treatment of osteoporosis.
Keywords
Date
2019
Type
Journal article
Journal
The Lancet Diabetes & Endocrinology
Book
Volume
7
Issue
12
Page Range
899-911
Article Number
ACU Department
Mary MacKillop Institute for Health Research
Faculty of Health Sciences
Collections
Mary MacKillop Institute for Health Research
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URI
https://hdl.handle.net/20.500.14802/23212
Relation URI
DOI
10.1016/S2213-8587(19)30346-8
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Open Access Status
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All rights reserved
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Controlled
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