{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T18:02:43Z","timestamp":1790791363335,"version":"4.1.0"},"reference-count":103,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2018,2,5]],"date-time":"2018-02-05T00:00:00Z","timestamp":1517788800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AG013918 R01"],"award-info":[{"award-number":["AG013918 R01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AR056679"],"award-info":[{"award-number":["AR056679"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"publisher","award":["I01 BX001405"],"award-info":[{"award-number":["I01 BX001405"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,3,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:sec>\n                  <jats:title>\u2003<\/jats:title>\n                  <jats:p>During the last 40 years, understanding of bone biology and the pathogenesis of osteoporosis, the most common and impactful bone disease of old age, has improved dramatically thanks to basic and clinical research advances, genetic insights from humans and rodents, and newer imaging technologies. Culprits of osteoporosis are no longer a matter of speculation based on in vitro observations. Instead, they can be identified and dissected at the cellular and molecular level using genetic approaches; and their effect on distinct bone envelopes and anatomic regions can be functionally assessed in vivo. The landscape of pharmacotherapies for osteoporosis has also changed profoundly with the emergence of several potent antiresorptive drugs as well as anabolic agents, displacing estrogen replacement as the treatment of choice. In spite of these major positive developments, the optimal duration of the available therapies and their long-term safety remain matters of conjecture and some concern. Moreover, antiresorptive therapies are used indiscriminately for patients of all ages on the assumption that suppressing remodeling is always beneficial for bone, but rebound remodeling upon their discontinuation suggests otherwise. In this invited perspective, I highlight the latest state of knowledge of bone-intrinsic and extrinsic mechanisms responsible for the development of osteoporosis in both sexes; differences between the mechanisms responsible for the effects of aging and estrogen deficiency; and the role of old osteocytes in the development of cortical porosity. In addition, I highlight advances toward the goal of developing drugs for several degenerative diseases of old age at once, including osteoporosis, by targeting shared mechanisms of aging. \u00a9 2018 American Society for Bone and Mineral Research.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1002\/jbmr.3400","type":"journal-article","created":{"date-parts":[[2018,2,5]],"date-time":"2018-02-05T19:38:40Z","timestamp":1517859520000},"page":"371-385","source":"Crossref","is-referenced-by-count":56,"title":["The Quest for Osteoporosis Mechanisms and Rational Therapies: How Far We've Come, How Much Further We Need to Go"],"prefix":"10.1093","volume":"33","author":[{"given":"Stavros C","family":"Manolagas","sequence":"first","affiliation":[{"name":"Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone DiseasesUniversity of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare SystemLittle RockARUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2018,2,5]]},"reference":[{"issue":"9696","key":"2024021014381396400_jbmr3400-bib-0001","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1016\/S0140-6736(09)61460-4","article-title":"Ageing populations: the challenges ahead","volume":"374","author":"Christensen","year":"2009","journal-title":"Lancet"},{"issue":"5","key":"2024021014381396400_jbmr3400-bib-0002","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1007\/s001980050093","article-title":"Updated data on proximal femur bone mineral levels of US adults","volume":"8","author":"Looker","year":"1998","journal-title":"Osteoporos Int"},{"issue":"9527","key":"2024021014381396400_jbmr3400-bib-0003","doi-asserted-by":"crossref","first-page":"2010","DOI":"10.1016\/S0140-6736(06)68891-0","article-title":"Osteoporosis","volume":"367","author":"Sambrook","year":"2006","journal-title":"Lancet"},{"issue":"5","key":"2024021014381396400_jbmr3400-bib-0004","doi-asserted-by":"crossref","first-page":"1917","DOI":"10.1007\/s00198-015-3458-6","article-title":"Rebound-associated vertebral fractures after discontinuation of denosumab-from clinic and biomechanics","volume":"27","author":"Popp","year":"2016","journal-title":"Osteoporos Int"},{"issue":"6","key":"2024021014381396400_jbmr3400-bib-0005","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1530\/EJE-16-1027","article-title":"Increased osteoclastogenesis in patients with vertebral fractures following discontinuation of denosumab treatment","volume":"176","author":"Anastasilakis","year":"2017","journal-title":"Eur J Endocrinol"},{"key":"2024021014381396400_jbmr3400-bib-0006","first-page":"99","article-title":"The two-stage concept of bone loss revisited","volume":"31","author":"Parfitt","year":"1992","journal-title":"Triangle"},{"issue":"9-10","key":"2024021014381396400_jbmr3400-bib-0007","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1016\/0094-5765(81)90082-5","article-title":"Bone effects of space flight: analysis by quantum concept of bone remodelling","volume":"8","author":"Parfitt","year":"1981","journal-title":"Acta Astronaut"},{"issue":"2","key":"2024021014381396400_jbmr3400-bib-0008","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1007\/BF02279116","article-title":"The cancellous bone of the iliac crest","volume":"4","author":"Wakamatsu","year":"1969","journal-title":"Calcif Tissue Res"},{"issue":"4","key":"2024021014381396400_jbmr3400-bib-0009","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/S0001-2998(87)80021-1","article-title":"Osteoporosis: the state of the art in 1987: a review","volume":"17","author":"Wasserman","year":"1987","journal-title":"Semin Nucl Med"},{"key":"2024021014381396400_jbmr3400-bib-0010","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1359\/jbmr.1998.13.5.763","article-title":"A unitary model for involutional osteoporosis: estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in aging men","volume":"13","author":"Riggs","year":"1998","journal-title":"J Bone Miner Res"},{"issue":"3","key":"2024021014381396400_jbmr3400-bib-0011","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1210\/er.2009-0024","article-title":"From estrogen-centric to aging and oxidative stress: a revised perspective of the pathogenesis of osteoporosis","volume":"31","author":"Manolagas","year":"2010","journal-title":"Endocr Rev"},{"issue":"3","key":"2024021014381396400_jbmr3400-bib-0012","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1001\/jama.288.3.321","article-title":"Writing Group for the Women's Health Initiative Investigators. 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