{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T12:51:03Z","timestamp":1773060663154,"version":"3.50.1"},"reference-count":40,"publisher":"The Endocrine Society","issue":"5","license":[{"start":{"date-parts":[[2021,1,25]],"date-time":"2021-01-25T00:00:00Z","timestamp":1611532800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Ministry of Health, Labour and Welfare of Japan"},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008644","name":"Japan Diabetes Society","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008644","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007664","name":"Manpei Suzuki Diabetes Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007664","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,4,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>To evaluate the effects of an intensified multifactorial intervention and patient characteristics on the incidence of fractures comorbid with type 2 diabetes.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Fracture events were identified and analyzed among adverse events reported in the J-DOIT3 study, a multicenter, open-label, randomized, parallel-group trial that was conducted in Japan, in which patients with type 2 diabetes were randomly assigned to receive conventional therapy for glucose, blood pressure, and lipids (targets: HbA1c\u2005&amp;lt;\u20056.9%, blood pressure &amp;lt;130\/80 mm Hg, LDL-cholesterol &amp;lt;120mg\/dL) or intensive therapy (HbA1c\u2005&amp;lt;\u20056.2%, blood pressure &amp;lt;120\/75 mm Hg, LDL-cholesterol &amp;lt;80mg\/dL) (ClinicalTrials.gov registration no. NCT00300976).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>The cumulative incidence of fractures did not differ between those receiving conventional therapy and those receiving intensive therapy (hazard ratio (HR) 1.15; 95% CI, 0.91-1.47; P\u2005=\u20050.241). Among the potential risk factors, only history of smoking at baseline was significantly associated with the incidence of fractures in men (HR 1.96; 95% CI, 1.04-3.07; P\u2005=\u20050.038). In contrast, the incidence of fractures in women was associated with the FRAX score [%\/10 years] at baseline (HR 1.04; 95% CI, 1.02-1.07; P\u2005&amp;lt;\u20050.001) and administration of pioglitazone at 1 year after randomization (HR 1.59; 95% CI, 1.06-2.38; P\u2005=\u20050.025).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Intensified multifactorial intervention may be implemented without increasing the fracture risk in patients with type 2 diabetes. The fracture risk is elevated in those with a history of smoking in men, whereas it is predicted by the FRAX score and is independently elevated with administration of pioglitazone in women.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1210\/clinem\/dgab013","type":"journal-article","created":{"date-parts":[[2021,1,25]],"date-time":"2021-01-25T18:55:58Z","timestamp":1611600958000},"page":"e2116-e2128","source":"Crossref","is-referenced-by-count":8,"title":["Effect of a Multifactorial Intervention on Fracture in Patients With Type 2 Diabetes: Subanalysis of the J-DOIT3 Study"],"prefix":"10.1210","volume":"106","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7644-309X","authenticated-orcid":false,"given":"Takayoshi","family":"Sasako","sequence":"first","affiliation":[{"name":"Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kohjiro","family":"Ueki","sequence":"additional","affiliation":[{"name":"Department of Molecular Diabetic Medicine, Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kana","family":"Miyake","sequence":"additional","affiliation":[{"name":"Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yukiko","family":"Okazaki","sequence":"additional","affiliation":[{"name":"Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan"},{"name":"Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuhiro","family":"Takeuchi","sequence":"additional","affiliation":[{"name":"Toranomon Hospital Endocrine Center, Tokyo, Japan"},{"name":"Okinaka Memorial Institute for Medical Research, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuo","family":"Ohashi","sequence":"additional","affiliation":[{"name":"Department of Integrated Science and Engineering for Sustainable Society, Chuo University, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mitsuhiko","family":"Noda","sequence":"additional","affiliation":[{"name":"Ichikawa Hospital, International University of Health and Welfare, Ichikawa, Japan"},{"name":"Department of Endocrinology and Diabetes, Saitama Medical University, Saitama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5428-3582","authenticated-orcid":false,"given":"Takashi","family":"Kadowaki","sequence":"additional","affiliation":[{"name":"Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan"},{"name":"Department of Prevention of Diabetes and Lifestyle-Related Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan"},{"name":"Toranomon Hospital, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"80","published-online":{"date-parts":[[2021,1,25]]},"reference":[{"key":"2021122204522576000_CIT0001","doi-asserted-by":"crossref","first-page":"690783","DOI":"10.1155\/2014\/690783","article-title":"The alliance of mesenchymal stem cells, bone, and diabetes","volume":"2014","author":"Napoli","year":"2014","journal-title":"Int J Endocrinol."},{"issue":"2","key":"2021122204522576000_CIT0002","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1007\/s00223-016-0226-3","article-title":"Pathophysiology of bone fragility in patients with diabetes","volume":"100","author":"Palermo","year":"2017","journal-title":"Calcif Tissue Int."},{"issue":"12","key":"2021122204522576000_CIT0003","doi-asserted-by":"crossref","first-page":"2585","DOI":"10.1007\/s00198-018-4650-2","article-title":"Diagnosis and management of bone fragility in diabetes: an emerging challenge","volume":"29","author":"Ferrari","year":"2018","journal-title":"Osteoporos Int."},{"key":"2021122204522576000_CIT0004","author":"FRAX\u00ae Fracture Risk Assessment Tool."},{"issue":"21","key":"2021122204522576000_CIT0005","doi-asserted-by":"crossref","first-page":"2184","DOI":"10.1001\/jama.2011.715","article-title":"Association of BMD and FRAX score with risk of fracture in older adults with type 2 diabetes","volume":"305","author":"Schwartz","year":"2011","journal-title":"JAMA."},{"issue":"2","key":"2021122204522576000_CIT0006","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1002\/jbmr.556","article-title":"FRAX underestimates fracture risk in patients with diabetes","volume":"27","author":"Giangregorio","year":"2012","journal-title":"J Bone Miner Res."},{"key":"2021122204522576000_CIT0007","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.bone.2014.08.010","article-title":"Risk of fracture with thiazolidinediones: an updated meta-analysis of randomized clinical trials","volume":"68","author":"Zhu","year":"2014","journal-title":"Bone."},{"issue":"10","key":"2021122204522576000_CIT0008","doi-asserted-by":"crossref","first-page":"3621","DOI":"10.1210\/jc.2017-00042","article-title":"Type 2 diabetes and osteoporosis: a guide to optimal management","volume":"102","author":"Paschou","year":"2017","journal-title":"J Clin Endocrinol Metab."},{"issue":"6","key":"2021122204522576000_CIT0009","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1172\/JCI200419900","article-title":"PPARgamma insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors","volume":"113","author":"Akune","year":"2004","journal-title":"J Clin Invest."},{"issue":"6","key":"2021122204522576000_CIT0010","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1172\/JCI21311","article-title":"Fat\u2019s loss is bone\u2019s gain","volume":"113","author":"Pei","year":"2004","journal-title":"J Clin Invest."},{"issue":"2","key":"2021122204522576000_CIT0011","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1210\/er.2012-1042","article-title":"The impact of diabetes and diabetes medications on bone health","volume":"36","author":"Gilbert","year":"2015","journal-title":"Endocr Rev."},{"issue":"23","key":"2021122204522576000_CIT0012","doi-asserted-by":"crossref","first-page":"2427","DOI":"10.1056\/NEJMoa066224","article-title":"Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy","volume":"355","author":"Kahn","year":"2006","journal-title":"N Engl J Med."},{"issue":"3","key":"2021122204522576000_CIT0013","doi-asserted-by":"crossref","first-page":"187","DOI":"10.2165\/00002018-200932030-00002","article-title":"Safety and tolerability of pioglitazone in high-risk patients with type 2 diabetes: an overview of data from PROactive","volume":"32","author":"Dormandy","year":"2009","journal-title":"Drug Saf."},{"issue":"11","key":"2021122204522576000_CIT0014","doi-asserted-by":"crossref","first-page":"2142","DOI":"10.2337\/dc15-1068","article-title":"Incidence of fractures in patients with type 2 diabetes in the SAVOR-TIMI 53 trial","volume":"38","author":"Mosenzon","year":"2015","journal-title":"Diabetes Care."},{"issue":"11","key":"2021122204522576000_CIT0015","doi-asserted-by":"crossref","first-page":"4059","DOI":"10.1210\/jc.2015-1215","article-title":"Effects of TZD use and discontinuation on fracture rates in ACCORD bone study","volume":"100","author":"Schwartz","year":"2015","journal-title":"J Clin Endocrinol Metab."},{"issue":"3","key":"2021122204522576000_CIT0016","first-page":"914","article-title":"Pioglitazone and risk for bone fracture: safety data from a randomized clinical trial","volume":"102","author":"Viscoli","year":"2017","journal-title":"J Clin Endocrinol Metab."},{"issue":"1","key":"2021122204522576000_CIT0017","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1111\/dom.12786","article-title":"Sitagliptin and risk of fractures in type 2 diabetes: Results from the TECOS trial","volume":"19","author":"Josse","year":"2017","journal-title":"Diabetes Obes Metab."},{"issue":"1","key":"2021122204522576000_CIT0018","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1210\/jc.2015-3167","article-title":"Effects of canagliflozin on fracture risk in patients with type 2 diabetes mellitus","volume":"101","author":"Watts","year":"2016","journal-title":"J Clin Endocrinol Metab."},{"issue":"7","key":"2021122204522576000_CIT0019","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.2337\/dc11-2184","article-title":"Intensive glycemic control is not associated with fractures or falls in the ACCORD randomized trial","volume":"35","author":"Schwartz","year":"2012","journal-title":"Diabetes Care."},{"issue":"12","key":"2021122204522576000_CIT0020","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.1007\/s11606-014-2961-3","article-title":"Intensive blood pressure control, falls, and fractures in patients with type 2 diabetes: the ACCORD trial","volume":"29","author":"Margolis","year":"2014","journal-title":"J Gen Intern Med."},{"issue":"11","key":"2021122204522576000_CIT0021","doi-asserted-by":"crossref","first-page":"2278","DOI":"10.1002\/jbmr.3214","article-title":"The effect of intentional weight loss on fracture risk in persons with diabetes: results from the look AHEAD randomized clinical trial","volume":"32","author":"Johnson","year":"2017","journal-title":"J Bone Miner Res."},{"issue":"11","key":"2021122204522576000_CIT0022","doi-asserted-by":"crossref","first-page":"1587","DOI":"10.1111\/dom.12983","article-title":"Safety of sitagliptin in patients with type 2 diabetes and chronic kidney disease: outcomes from TECOS","volume":"19","author":"Engel","year":"2017","journal-title":"Diabetes Obes Metab."},{"issue":"4","key":"2021122204522576000_CIT0023","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1359\/jbmr.081207","article-title":"Diabetic patients have an increased risk of vertebral fractures independent of BMD or diabetic complications","volume":"24","author":"Yamamoto","year":"2009","journal-title":"J Bone Miner Res."},{"issue":"12","key":"2021122204522576000_CIT0024","doi-asserted-by":"crossref","first-page":"2925","DOI":"10.1185\/03007990903328124","article-title":"Long-term effects of pioglitazone in Japanese patients with type 2 diabetes without a recent history of macrovascular morbidity","volume":"25","author":"Kaku","year":"2009","journal-title":"Curr Med Res Opin."},{"issue":"1","key":"2021122204522576000_CIT0025","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/nm0106-73","article-title":"Combating diabetes and obesity in Japan","volume":"12","author":"Yazaki","year":"2006","journal-title":"Nat Med."},{"issue":"1","key":"2021122204522576000_CIT0026","doi-asserted-by":"crossref","first-page":"e000123","DOI":"10.1136\/bmjdrc-2015-000123","article-title":"Design of and rationale for the Japan Diabetes Optimal Integrated Treatment study for 3 major risk factors of cardiovascular diseases (J-DOIT3): a multicenter, open-label, randomized, parallel-group trial","volume":"4","author":"Ueki","year":"2016","journal-title":"BMJ Open Diabetes Res Care."},{"issue":"12","key":"2021122204522576000_CIT0027","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1016\/S2213-8587(17)30327-3","article-title":"Effect of an intensified multifactorial intervention on cardiovascular outcomes and mortality in type 2 diabetes (J-DOIT3): an open-label, randomised controlled trial","volume":"5","author":"Ueki","year":"2017","journal-title":"Lancet Diabetes Endocrinol."},{"key":"2021122204522576000_CIT0028","doi-asserted-by":"crossref","DOI":"10.1016\/j.kint.2020.08.012","article-title":"Multifactorial intervention has a significant effect on diabetic kidney disease in patients with type 2 diabetes","author":"Ueki","year":"2021","journal-title":"Kidney Int."},{"key":"2021122204522576000_CIT0029","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1007\/s13340-015-0206-2","article-title":"Evidence-based practice guideline for the treatment for diabetes in Japan 2013","volume":"6","author":"Tajima","year":"2015","journal-title":"Diabetol Int."},{"key":"2021122204522576000_CIT0030","author":"ClinicalTrials.gov."},{"key":"2021122204522576000_CIT0031","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s11657-012-0109-9","article-title":"Japanese 2011 guidelines for prevention and treatment of osteoporosis\u2013executive summary","volume":"7","author":"Orimo","year":"2012","journal-title":"Arch Osteoporos."},{"issue":"3","key":"2021122204522576000_CIT0032","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/S2213-8587(19)30422-X","article-title":"Association of glucose-lowering medications with cardiovascular outcomes: an umbrella review and evidence map","volume":"8","author":"Zhu","year":"2020","journal-title":"Lancet Diabetes Endocrinol."},{"issue":"12","key":"2021122204522576000_CIT0033","doi-asserted-by":"crossref","first-page":"3037","DOI":"10.1007\/s00198-011-1537-x","article-title":"Fracture risk prediction using FRAX\u00ae: a 10-year follow-up survey of the Japanese Population-Based Osteoporosis (JPOS) Cohort Study","volume":"22","author":"Tamaki","year":"2011","journal-title":"Osteoporos Int."},{"issue":"6","key":"2021122204522576000_CIT0034","doi-asserted-by":"crossref","first-page":"1841","DOI":"10.1007\/s00198-015-3092-3","article-title":"Trabecular bone score may improve FRAX\u00ae prediction accuracy for major osteoporotic fractures in elderly Japanese men: the Fujiwara-kyo Osteoporosis Risk in Men (FORMEN) Cohort Study","volume":"26","author":"Iki","year":"2015","journal-title":"Osteoporos Int."},{"issue":"2","key":"2021122204522576000_CIT0035","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1007\/s00198-004-1640-3","article-title":"Smoking and fracture risk: a meta-analysis","volume":"16","author":"Kanis","year":"2005","journal-title":"Osteoporos Int."},{"issue":"10","key":"2021122204522576000_CIT0036","doi-asserted-by":"crossref","first-page":"2057","DOI":"10.1007\/s00125-014-3289-6","article-title":"Fracture risk in diabetic elderly men: the MrOS study","volume":"57","author":"Napoli","year":"2014","journal-title":"Diabetologia."},{"issue":"1","key":"2021122204522576000_CIT0037","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1002\/jbmr.3287","article-title":"Vertebral fracture risk in diabetic elderly men: the MrOS study","volume":"33","author":"Napoli","year":"2018","journal-title":"J Bone Miner Res."},{"issue":"10","key":"2021122204522576000_CIT0038","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.2105\/AJPH.88.10.1481","article-title":"Ex-smokers and risk of hip fracture","volume":"88","author":"Fors\u00e9n","year":"1998","journal-title":"Am J Public Health."},{"issue":"5","key":"2021122204522576000_CIT0039","doi-asserted-by":"crossref","first-page":"1645","DOI":"10.1210\/jc.2018-01879","article-title":"Association between glycemic control and risk of fracture in diabetic patients: a nested case-control study","volume":"104","author":"Vavanikunnel","year":"2019","journal-title":"J Clin Endocrinol Metab."},{"issue":"9","key":"2021122204522576000_CIT0040","doi-asserted-by":"crossref","first-page":"2060","DOI":"10.2337\/dc20-0316","article-title":"Severe hypoglycemia and risk of falls in type 2 diabetes: The Atherosclerosis Risk in Communities (ARIC) Study","volume":"43","author":"Lee","year":"2020","journal-title":"Diabetes Care."}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jcem\/advance-article-pdf\/doi\/10.1210\/clinem\/dgab013\/36094142\/dgab013.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jcem\/article-pdf\/106\/5\/e2116\/41847638\/dgab013.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jcem\/article-pdf\/106\/5\/e2116\/41847638\/dgab013.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,22]],"date-time":"2021-12-22T04:54:34Z","timestamp":1640148874000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/106\/5\/e2116\/6118653"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,25]]},"references-count":40,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,1,25]]},"published-print":{"date-parts":[[2021,4,23]]}},"URL":"https:\/\/doi.org\/10.1210\/clinem\/dgab013","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,5,1]]},"published":{"date-parts":[[2021,1,25]]}}}