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Lancet Diabetes Endocrinol. 2019 Dec;7(12):899-911. doi: 10.1016/S2213-8587(19)30346-8. Epub 2019 Oct 31.

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

Collaborators (373)

Mautalén CA, Man Z, Zanchetta JR, Magaril CH, Sambrook P, Reginster JY, Geusens P, Goemaere S, Albergaria BH, Zerbini CAF, Castro ML, Gregorio LH, Stoilov R, Borissova AI, Hristozov KH, Temelkova NL, Daskalova IK, Kuzmanova SI, Yaneva-Bichovska D, Batalov AZ, Riedemann P, Rodriguez Portales JA, Tang H, Zhu H, Zhang Z, Chao A, Hu Y, Liu Z, Lu J, Qiu M, Gao X, Zhang S, Xu L, Xia W, Liao E, Yang W, Wu W, Dai K, Hu R, Tang H, Jaller JJ, Cabal F, Molina JF, Cure Cure CA, Yupanqui-Lozno H, Chalem P, Londono J, Abello M, Tobias ED, Otero W, Nikolic T, Miskic B, Stepan J, Vyskocil V, Novosad L, Slesinger J, Novosad P, Vlckova E, Bortlik L, Dokoupilova E, Hala T, Jensen JB, Brixen KT, Langdahl BL, Schwarz P, Eskildsen PC, Eiken PA, Hermann AP, Gram J, Schou MB, Alexandersen P, Nedergaard B, Mejía DM, Estrella De Henriquez L, Páez N, Velazco C, Valter I, Vahula KL, Kull I, Maasalu K, Chapurlat R, Fardellone P, Benhamou CL, Roux C, Weryha G, Herkt V, Martz R, Nischik R, Spieler W, Contzen C, Felsenberg D, Frieling I, Frahm E, Briones H, Sandoval B, Barrios P, García A, Avendaño C, González M, Guerra J, Tuna M, Díaz OM, Samayoa E, López E, Barrera JR, Palencia M, Cifuentes M, Alvarado G, López M, Chavez N, Haase F, Rivera R, González C, Tan K, Leung PC, Mandalam S, Pitale SU, Bantwal G, Ammini AC, Shaikh SSA, Kanakatte Mylariah PK, Dharmalingam M, Mukhopadhyay S, Jain A, Singh P, Shetty N, Sathyanarayana SS, Shah N, Chadha MD, Bhandankar R, Velayutham K, Marwah S, John M, Sahay RK, Adami S, Nuti R, Bianchi G, Brandi ML, Minisola S, Fiore CE, Rubinacci A, Miyajima H, Yamane H, Nakatani Y, Okamoto S, Kuroda K, Fujimori M, Itabashi A, Katayama K, Nakajo S, Somekawa Y, Ohsawa Y, Tajima W, Mizuno K, Mori S, Kanabuchi T, Hashizume H, Oka N, Hamada K, Yamaguchi M, Hirahara F, Atobe M, Ohtake Y, Ichikawa S, Onishi T, Matsumoto K, Nakamura T, Shirasawa E, Katayama K, Takahashi M, Oguma T, Matsui H, Katoh Y, Shigenobu K, Onishi T, Shibukawa M, Ikeda S, Osaka K, Kanda R, Inobe Y, Shigenobu M, Hasegawa M, Yamaji T, Miyazaki Y, Ito T, Nakamura E, Nagai S, Lim SK, Chung YS, Shin CS, Min YK, Kim GS, Yoon HK, Kang MI, Yang KH, Park HM, Kim IJ, Chung DJ, Chung HY, Jaundzeikare S, Andersone D, Medne A, Yaghi Y, Alekna V, Kasiulevicius V, Purtokaite-Labutiniene I, Krasauskiene A, Varanaviciene J, Basijokiene V, Abraitiene A, Radzeviciene L, Walliser J, García Hernández PA, Araujo MF, Avila Armengol HE, De la Peña P, Tamayo J, Zazueta B, Cons F, Gilchrist NL, Reid IR, Leikis R, Jones P, Singh JGP, Halse JI, Syversen U, Høivik HO, Øfjord ES, Gulseth HC, Elle S, Norheim PD, Calvo Quiroz AA, Cesar Augusto PA, León Portocarrero MG, Vidal Neira LF, Chavez J, Garro Barrera B, Kuroiwa Sampei R, Luis Fernando BV, Oquelis Cabredo R, Castillo S, Morales AMG, Tan PP, Leagogo LAC Jr, Wang EH, Li-Yu JT, Sawicki AZ, Stasiuk B, Kania G, Lorenc R, Sidorowicz-Bialynicka A, Szczepanski L, Franek E, Filip R, Sekula J, Blicharski T, Leszczynski P, Sewerynek E, Miazgowski T, Milewicz A, Dabrowska M, Romaszko J, Pluskiewicz W, Wojnowski L, Codreanu C, Bolosiu H, Ionescu R, Zosin I, Macovei L, Bojinca M, Radulescu F, Pop S, Sarbu A, Benevolenskaya LI, Nasonov EL, Rozhinskaya LY, Oganov RG, Rodionova SS, Shlyakhto EV, Trofimov V, Zotkin EG, Zazerskaya IE, Grineva EN, Ershova O, Lesnyak O, Ostroumova OD, Malichenko SB, Pikhlak EG, Pilyaev VG, Raskina T, Zonova EV, Shirinsky VS, Dimic AN, Cobeljic G, Vujovic S, Ellis GC, Lipschitz S, De Villiers TJ, De Weerd AJ, Vally T, Trinder Y, Coetsee JL, Davis CP, Nayiager S, Hough FS, Oelofse LF, van der Walt E, Lombaard JJ, Blignaut S, Govind U, Fouche LF, Kruger DS, Dalmeyer JP, Ferreira MM, Escudero-Contreras A, Muñoz Torres M, Hawkins Carranza F, Perez Castrillon JL, García Meijide JA, Jodar Gimeno E, Palacios Gil-Antuñana S, de Teresa Parreno L, Martín Mola E, Alvarez Sanchez C, Lippuner K, Tsai KS, Tu ST, Chen JF, Lee OK, Hsu WW, Grygorieva NV, Povoroznyuk VV, Korzh MO, Loskutov OL, Chukov AB, Sarmiento R, Thomas H, Donnachie H, Pavel-Knox I, Shaw H, Hassanin H, Abdulhakim EEA, Savani N, Bachmann GA, Barrett-Connor E, Binkley NC, Bone HG, Brandon DM, Checketts DD, Fraser NJ, Watts NB, Geller SA, Gimbel JS, Greenwald MW, Holt PA, Johnston CC, Fang C, Kiel DP, Klashman DJ, Lewiecki EM, Lowenstein MB, McClung MR, Nattrass SM, Odio A, Levengood J, Romaguera J, Saag KG, Sebai MB, Snyder B, Kutner ME, Streja D, Schwartz EP, Christiansen MG.

Author information

1
Oregon Osteoporosis Center, Portland, OR, USA; Mary MacKillop Center for Health Research, Australian Catholic Unversity, Melbourne, VIC, Australia.
2
Thrombolysis in Myocardial Infarction Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, USA.
3
Leiden University Medical Center, Leiden, Netherlands.
4
Michigan Bone and Mineral Clinic, Detroit, MI, USA.
5
Aarhus University Hospital, Aarhus, Denmark.
6
University of Alabama at Birmingham, Birmingham, AL, USA.
7
University of Auckland, Auckland, New Zealand.
8
Institute for Aging Research, Hebrew SeniorLife, Harvard Medical School, Boston, MA, USA.
9
Stellenbosch University, Stellenbosch, South Africa.
10
Peking Union Medical College, Dongcheng, Beijing, China.
11
Bern University Hospital, University of Bern, Bern, Switzerland.
12
University of Occupational and Environmental Health, Kitakyushu, Japan.
13
Department of Public Health, Epidemiology and Health Economics and WHO Collaborating Centre for Public Health Aspects of Musculoskeletal Health and Aging, University of Liège, Liège, Belgium.
14
Pontifical Catholic University of Chile, Santiago, Chile.
15
Paris Descartes University, Cochin Hospital, Paris, France.
16
Institute of Metabolic Research, Buenos Aires, Argentina.
17
Paulista Center of Investigations, São Paulo, Brazil.
18
Merck & Co, Inc, Kenilworth, NJ, USA.
19
Merck & Co, Inc, Kenilworth, NJ, USA. Electronic address: keith_kaufman@merck.com.

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.

FUNDING:

Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA.

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