{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T10:02:38Z","timestamp":1769594558963,"version":"3.49.0"},"reference-count":64,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2019,11,9]],"date-time":"2019-11-09T00:00:00Z","timestamp":1573257600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000033","name":"Institute of Musculoskeletal Health and Arthritis","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000033","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005622","name":"Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005622","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["asbmr.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["JBMR Plus"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Pathological bone loss is a regular feature of postmenopausal osteoporosis, and the microstructural changes along with the bone loss make the individual prone to getting hip, spine, and wrist fractures. We have developed a new conjugate drug named C3, which has a synthetic, stable EP4 agonist (EP4a) covalently linked to an inactive alendronate (ALN) that binds to bone and allows physiological remodeling. After losing bone for 12\u2009weeks, seven groups of rats were treated for 8\u2009weeks via tail\u2010vein injection. The groups were: C3 conjugate at low and high doses, vehicle\u2010treated ovariectomy (OVX) and sham, C1 (a similar conjugate, but with active ALN at high dose), inactive ALN alone, and a mixture of unconjugated ALN and EP4a to evaluate the conjugation effects. Bone turnover was determined by dynamic and static histomorphometry; \u03bcCT was employed to determine bone microarchitecture; and bone mechanical properties were evaluated via biomechanical testing. Treatment with C3 significantly increased trabecular bone volume and vertebral BMD versus OVX controls. There was also significant improvement in the vertebral load\u2010bearing abilities and stimulation of bone formation in femurs after C3 treatment. This preclinical research revealed that C3 resulted in significant anabolic effects on trabecular bone, and EP4a and ALN conjugation components are vital to conjugate anabolic efficacy. A combined therapy using an EP4 selective agonist anabolic agent linked to an inactive ALN is presented here that produces significant anabolic effects, allows bone remodeling, and has the potential for treating postmenopausal osteoporosis or other diseases where bone strengthening would be beneficial. \u00a9 2019 The Authors. <jats:italic>JBMR Plus<\/jats:italic> published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.<\/jats:p>","DOI":"10.1002\/jbm4.10237","type":"journal-article","created":{"date-parts":[[2019,9,16]],"date-time":"2019-09-16T15:59:08Z","timestamp":1568649548000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["In Vivo Bone Effects of a Novel Bisphosphonate\u2010EP4a Conjugate Drug (C3) for Reversing Osteoporotic Bone Loss in an Ovariectomized Rat Model"],"prefix":"10.1093","volume":"3","author":[{"given":"Zeeshan","family":"Sheikh","sequence":"first","affiliation":[{"name":"Lunenfeld\u2010Tanenbaum Research Institute Mount Sinai Hospital  Toronto Ontario Canada"},{"name":"Department of Laboratory Medicine and Pathology University of Toronto  Toronto Ontario Canada"},{"name":"Faculty of Dentistry University of Toronto  Toronto Ontario Canada"},{"name":"Faculty of Dentistry Dalhousie University  Halifax Nova Scotia Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Chemistry Simon Fraser University  Burnaby British Columbia Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Faik","family":"Al\u2010Jaf","sequence":"additional","affiliation":[{"name":"Faculty of Dentistry University of Toronto  Toronto Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marion","family":"Th\u00e9venin","sequence":"additional","affiliation":[{"name":"Department of Chemistry Simon Fraser University  Burnaby British Columbia Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kate","family":"Banks","sequence":"additional","affiliation":[{"name":"Division of Comparative Medicine University of Toronto  Toronto Ontario Canada"},{"name":"Department of Physiology University of Toronto  Toronto Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Glogauer","sequence":"additional","affiliation":[{"name":"Faculty of Dentistry University of Toronto  Toronto Ontario Canada"},{"name":"Department of Dental Oncology and Maxillofacial Prosthetics Princess Margaret Cancer Centre  Toronto Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert N","family":"Young","sequence":"additional","affiliation":[{"name":"Department of Chemistry Simon Fraser University  Burnaby British Columbia Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6726-6351","authenticated-orcid":false,"given":"Marc D","family":"Grynpas","sequence":"additional","affiliation":[{"name":"Lunenfeld\u2010Tanenbaum Research Institute Mount Sinai Hospital  Toronto Ontario Canada"},{"name":"Department of Laboratory Medicine and Pathology University of Toronto  Toronto Ontario Canada"},{"name":"Institute of Biomaterials and Biomedical Engineering University of Toronto  Toronto Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2019,11,9]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.2215\/CJN.04151206"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.beem.2018.09.005"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI111096"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.060104"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00198-018-4416-x"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2006.09.008"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.2001.16.1.157"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00198-007-0540-8"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.2005.20.7.1265"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1999.1499"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0093-7754(01)90259-3"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.85.11.6953"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.280.24.2077"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2004.12.004"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2006.04.028"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1620\/tjem.229.19"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1080\/01926230490462138"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1080\/01926230252929882"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1080\/01926230601072301"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1359\/JBMR.051023"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1053\/plac.2002.0948"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.5650100320"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/S8756-3282(97)00033-1"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1677\/joe.0.1680131"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1210\/endo.141.6.7518"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1210\/endo.140.4.6647"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/8756-3282(93)90183-B"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/8756-3282(90)90078-D"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00297302"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0169-6009(08)80230-9"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/S8756-3282(97)00147-6"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1677\/joe.0.1560051"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/0169-6009(92)90843-3"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/S8756-3282(98)00102-1"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00264-007-0406-x"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.5650080713"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2007.12.228"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2003.09.031"},{"issue":"8","key":"e_1_2_7_40_1","first-page":"1598","article-title":"Role of EP3 and EP4 prostaglandin receptors in reorganization of the cytoskeleton in mature human osteoclasts","volume":"31","author":"Sarrazin P","year":"2004","journal-title":"J Rheumatol."},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1054\/plef.1999.0127"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/S8756-3282(00)00447-6"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M002079200"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.062053399"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.051110"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/S8756-3282(01)00688-3"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.60.1.36"},{"key":"e_1_2_7_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2003.09.008"},{"key":"e_1_2_7_49_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00198-015-3284-x"},{"key":"e_1_2_7_50_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.2382"},{"key":"e_1_2_7_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bonr.2018.06.007"},{"key":"e_1_2_7_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2012.01.024"},{"key":"e_1_2_7_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coph.2018.03.010"},{"key":"e_1_2_7_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/0169-6009(91)90124-I"},{"key":"e_1_2_7_55_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02571317"},{"key":"e_1_2_7_56_1","doi-asserted-by":"publisher","DOI":"10.3109\/10520299209110002"},{"key":"e_1_2_7_57_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.1805"},{"key":"e_1_2_7_58_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02555700"},{"key":"e_1_2_7_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/8756-3282(86)90683-6"},{"key":"e_1_2_7_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2005.03.016"},{"key":"e_1_2_7_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/8756-3282(90)90057-6"},{"key":"e_1_2_7_62_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2006-2023H"},{"key":"e_1_2_7_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-894X(03)00042-8"},{"key":"e_1_2_7_64_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02554834"},{"key":"e_1_2_7_65_1","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.2000.15.4.613"}],"container-title":["JBMR Plus"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjbm4.10237","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jbm4.10237","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jbm4.10237","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jbm4.10237","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,14]],"date-time":"2024-03-14T13:54:54Z","timestamp":1710424494000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmrplus\/article\/7479105"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,9]]},"references-count":64,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2019,12]]}},"alternative-id":["10.1002\/jbm4.10237"],"URL":"https:\/\/doi.org\/10.1002\/jbm4.10237","archive":["Portico"],"relation":{},"ISSN":["2473-4039","2473-4039"],"issn-type":[{"value":"2473-4039","type":"print"},{"value":"2473-4039","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,9]]},"assertion":[{"value":"2019-04-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-09-06","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-11-09","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e10237"}}